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Contents lists available at ScienceDirect

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Review

RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions Patrizia D’Adamo a,b,∗ , Michela Masetti a , Veronica Bianchi a,b , Lorenzo Morè a , Maria Lidia Mignogna a,b , Maila Giannandrea a,c , Silvia Gatti c a

Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Neuroscience, via Olgettina 58, 20132 Milan, Italy Vita-Salute San Raffaele University, via Olgettina 58, 20132 Milan, Italy c F. Hoffmann-La Roche AG, pRED Pharma Research & Early Development, DTA Neuroscience Grenzacherstrasse 124, Basel CH4070, Switzerland b

a r t i c l e

i n f o

Article history: Received 14 August 2013 Received in revised form 15 November 2013 Accepted 16 December 2013 Keywords: RAB GTPase Intellectual disability Brain development GDI1 G proteins

a b s t r a c t A RAS-related class of small monomeric G proteins, the RAB GTPases, is emerging as of key biological importance in compartment specific directional control of vesicles formation, transport and fusion. Thanks to human genetic observation and to the consequent dedicated biochemical work, substantial progress has been made on the understanding of the role played by RAB GTPases and their effector proteins on neuronal development and the shaping of cognitive functions. This review is highlighting these initial elements to broaden the current scope of research on developmental cognitive deficits and take the point of view of RAB GTPases control on membrane transport in neurons and astrocytes. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

4. 5.

6. 7.

8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RAB GTPases biochemical properties, structural domains and role of interacting proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RAB GTPases functions in neurons and astrocytes: from cargo recognition to receptor desensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. ER–Golgi vesicle trafficking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Synaptic vesicles fusion and endocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Axonal and dendritic transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Neurite morphogenesis and outgrowth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Metabolic/trophic role of RABs in glial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain expression of RAB GTPases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Developmental aspects of the biology of RAB GTPases in the central nervous system and deficits in neurodevelopmental disorders . . . . . . . . . . . . 5.1. X-linked forms of intellectual disability (XLID) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Autism spectrum disorders (ASD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Deficit in RAB and RAB interacting proteins in human neurological diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RAB GTPases related mouse models: assessment of cognitive deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. RAB3 family animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Gdi1 mouse models and cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspective and potential therapeutic strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: Dulbecco Telethon Institute at San Raffaele Scientific Institute, Division of Neuroscience, Via Olgettina 58, 20132 Milan, Italy. Tel.: +39 02 26434604; fax: +39 02 26434844. E-mail address: [email protected] (P. D’Adamo). 0149-7634/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neubiorev.2013.12.009

Please cite this article in press as: D’Adamo, P., et al., RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2013.12.009

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1. Introduction Up to now, about 70 human RAB GTPases are known, they are subdivided into 44 families and only for a handful of them the function in the CNS is clearly demonstrated (see Table 1). The discovery of the first RAB GTPase protein in yeast (YPT) was fortuitous, while studying an open reading frame between the tubulin and actin genes in the yeast genome. Soon after, the first 4 RAB GTPase proteins were cloned from rat brain tissue cDNA libraries (Touchot et al., 1987), and in within few years their function was linked to endo- and exocytosis, tubulin and actin mediated movement along microfilaments, synaptic release dynamics and vesicle coat components like SNAREs. In 1998 came the first observation of a genetic link between specific RAB GTPases (and interacting proteins) and developmental disorders (Bienvenu et al., 1998; D’Adamo et al., 1998) and this forced to reconsider the specific function of RAB GTPases in the central nervous system (CNS) (Ng and Tang, 2008) and triggered a more general interest on the development of null mutants mouse models for behavioural studies. The role of each RAB GTPase is usually specific and compartment dependent (Zerial and McBride, 2001). A classic example of this, in the CNS, is the control exerted by different RABs on the neuronal transport of AMPA receptor subunits. The transport of AMPA-type glutamate receptors into synapses occurs in fact in discrete steps: RAB11-dependent endosomes translocate AMPA receptor subunits from the dendritic shaft into spines. Subsequently, an additional endosomal trafficking step, controlled by RAB8, drives receptor insertion into the synaptic membrane during constitutive cycling and long-term potentiation (LTP). Separate from this receptor delivery route is the constitutive endosomal recycling of AMPA receptor subunits within the spine, which is controlled by RAB4. And, in addition, RAB5 is specifically activated by NMDA induced long-term depression (LTD) to cause the internalization of both GluA1 and GluA2 AMPA receptor subunits (Brown et al., 2007; Gerges et al., 2004, 2005). What really defines RAB GTPases function in a given sub-cellular system is the effector protein that interacts with the GTP-bound active state of RABs and lead to a final effect. This general mechanism of multiple interactions can span across classes of proteins and create different levels of cross talk even with receptor mediated signalling pathways. An example is Optineurin: an effector protein for activated RAB8 which can interact with the C-terminal tail of GPCRs (e.g. mGlu1a receptor) and mediate attenuation of signal transduction and endocytosis in an agonist dependent manner (Esseltine et al., 2012). A status update on brain expressed RAB GTPases, as well as their interacting proteins, is presented in this review with a focus on the role played by these proteins on neurobiological events known to affect cognitive functions. The main aim is to provide an overview of the on-going effort of characterization of RAB GTPases in the CNS and a perspective on what this may bring to our current understanding of brain development and intellectual disabilities. 2. RAB GTPases biochemical properties, structural domains and role of interacting proteins All RAB GTPases contain GDP/GTP binding domains, exhibit GTPase enzymatic activity and are segregated in specific cellular compartments. They are subdivided on the basis of primary sequence homology and possibly gene duplication events during evolution (Elias, 2010). Subfamilies of closely related RAB proteins exhibit 75–95% aminoacidic sequence identity and substantial overlapping functions (Pereira-Leal and Seabra, 2001). RAB GTPases have been found in all eukaryotes from S. cerevisiae, to D. melanogaster and mammals. Their large number and wide distribution in several species highlights their importance in eukaryotic

Fig. 1. Crystal structure of a RAB protein in its GTP-bound state. A cartoon representation of SGTP Sec4 is shown. TP is red, whereas P-loop (G-box2) is yellow, switch1 (G-box2) is light-blue, inter-switch is green, switch 2 (holding the G-box 3) is magenta, G-box4 and G-box5 are blue and violet, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)

cell function (Stenmark, 2009). Three different classes of regulatory proteins modulate the guanine nucleotide binding status of RABs: namely the guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs) (Cherfils and Zeghouf, 2013). As shown in Fig. 1, RABs consists of a compact, globular, GTP binding and hydrolysis domain, linked to an unstructured, hypervariable C-terminal domain containing the targeting signal to membranes upon isoprenoid modification (by prenyl transferases) (Itzen and Goody, 2011). The hydrophobic geranylgeranyl group can be inserted only when in the presence of RAB escort protein (REP) able to present the RABs to the transferase and to deliver the geranylgeranylated RAB GTPases to the membrane. Membrane bound GDI displacement factors (GDF) are helping proper targeting and membrane insertion. RAB cognate Guanine nucleotide Exchange Factors (GEFs), enhance release of GDP and facilitate RABs transition to the GTP-bound activated state (Barr and Lambright, 2010). At this point, activated RABs interact with the effector proteins, recruited to target membrane surfaces (compartments) and required to form a stable ternary complex (effector–RAB–GTP). The effector protein is going to carry out the downstream functions of individual RAB proteins. Specific effector molecules could be sorting adaptors, tethering factors, kinases, phosphatases and motor proteins. The effectors bind to the domain of RABs (GTP binding containing switch and inter-switch regions, Fig. 1 in light-blue, magenta and green, respectively) that changes conformation between active and inactive state. RABs stabilized in the ternary complex exhibit intrinsic GTPase activity and GTP hydrolysis is also accelerated by GTPase-activating proteins (GAPs) (Barr and Lambright, 2010; Fukuda, 2011). The role of GAPs is to accelerate the inactivation process and ordered GAP recruitment is part of the mechanisms that enhance fidelity of RABs segregation in different membrane compartments. RAB GEFs and GAPs proteins typically fall into discrete families defined by conserved protein domains. Among GAPs are TBC-domain containing proteins (Frasa et al., 2012) while RAB GEFs may contain different domains (DENN-; TRAPP-I complex; Vps9; Sec2p/Rabin domains among others). Once in the inactive GDP-bound state, a negative regulator known as RAB GDP dissociation inhibitor (␣ and ␤GDI) binds RABs. These inhibitors are involved in retrieving the inactive GDP-bound RAB GTPases from membranes and in maintaining a cytosolic pool of GDP associated prenylated RABs by blocking GDP

Please cite this article in press as: D’Adamo, P., et al., RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2013.12.009

Reference

Associated disease

Reference

RAB1 RAB3A RAB3B RAB3C

ER–Golgi trafficking Synaptic vesicle exocytosis; astrocytes and oligodendrocytes trafficking (RAB3A)

Allan et al. (2000) Anitei et al. (2009), Chen et al. (2013), Geppert et al. (1994, 1997), Martelli et al. (2000), Schluter et al. (2002), Tsetsenis et al. (2011)

Parkinson Warburg micro and Martsolf syndromes; Parkinson; Huntington’s disease; Myotonic dystrophy type 1

Cooper et al. (2006) Aligianis et al. (2005), Borck et al. (2011), Handley et al. (2013), Hernandez-Hernandez et al. (2013), Morton et al. (2001)

RAB4A

Sorting and endocytic recycling to the PM Critical importance for neuronal spine size Early endosome fusion Axonal retrograde transport and endosomal sorting AMPAR endocytosis Retrograde Golgi–ER transport Rhodopsin trafficking in photoreceptor cells Intra-Golgi transport. Highly expressed in microglia, pericytes and Purkinje neurons Late endosomes to lysosome. Controls axonal retrograde transport

Brown et al. (2007), Mohrmann et al. (2002), Odley et al. (2004) Brown et al. (2005), Bucci et al. (1992), Deinhardt et al. (2006), Fischer von Mollard et al. (1994b), Shimizu et al. (2003) Darchen and Goud (2000), Opdam et al. (2000), Shetty et al. (1998), Wanschers et al. (2007)

Alzheimer’s disease; Down’s syndrome; Niemann–Pick disease Alzheimer’s disease; Amyotrophic lateral sclerosis 2; Huntigton’s disease; Parkinson

Choudhury et al. (2002), Ginsberg et al. (2011) Ginsberg et al. (2011), Lai et al. (2009), Nath et al. (2012), Pal et al. (2008)

Alzheimer’s disease

Elfrink et al. (2012)

Cogli et al. (2013), Deinhardt et al. (2006), Gutierrez et al. (2004), Vanlandingham and Ceresa (2009)

BasuRay et al. (2013), Cogli et al. (2013), Houlden et al. (2004), Luiro et al. (2004), Meggouh et al. (2006), Palmisano et al. (2011)

RAB8B

Trans Golgi network-recycling endosomes-PM Controls neurite outgrowth. AMPAR trafficking. mGluR1a intracellular trafficking

RAB9B RAB11A RAB11B

Trans Golgi network Recycling endosome Recycling of extracellular alpha-synuclein. Involved in neurite formation. AMPA trafficking. Neuronal glucose uptake Early endocytic trafficking Recycling endosome Involved in dendritic morphogenesis and post-synaptic development ER-Golgi trafficking Regulates secretion in neuroendocrine cells Endosomal transport Involved in oligodendrocytes transport Role in Ca2+ -dependent-exocytosis of glutamate. Involved in glutamate transporter surface expression in astrocyte PM transport Involved in development of neural tube Exocytic pathway Modulates cell surface transport of ␣2-adrenergic receptors from Golgi Secretory pathways Possible involvement in ciliary transport in photoreceptor cells Golgi trafficking Mediates anterograde vesicular transport for membrane exocytosis and axon outgrowth Golgi trafficking Neurite extension and synapse formation and/or stabilization Golgi, recycling endosomes Involved in oligodendrocytes vesicle transport

Brown et al. (2007), Deretic et al. (1995), Esseltine et al. (2012), Gerges et al. (2004), Huber et al. (1995), Huber et al. (1993), Moritz et al. (2001), van Ijzendoorn et al. (2003) Ganley et al. (2004), Lombardi et al. (1993) Brown et al. (2007), Chen et al. (1998), Khvotchev et al. (2003), Li et al. (2009, 2012b), Shirane and Nakayama (2006)

Huntington’s disease; Charcot–Marie–Tooth type 2B disease Niemann–Pick disease; Alzheimer’s disease Sporadic amyotrophic lateral sclerosis; Batten disease Huntington’s disease; Parkinson; glaucoma (retinal degeneration)

RAB5

RAB6A RAB6B

RAB7

RAB15 RAB17

RAB18 RAB22B

RAB23 RAB26

RAB27A RAB28 RAB33A

RAB39B

RAB40C

Chi et al. (2010), Dalfo et al. (2004), del Toro et al. (2009), Gitler et al. (2008)

Niemann–Pick type C; Batten Disease Huntington’s disease; Parkinson’s disease; Batten disease; Charcot–Marie–Tooth type 4C disease

Luiro et al. (2004), Narita et al. (2005) Li et al. (2009, 2012b), Luiro et al. (2004), Roberts et al. (2010), Steinert et al. (2012)

Warburg micro syndrome

Handley et al. (2013)

Eggenschwiler et al. (2006), Eggenschwiler et al. (2001) Li et al. (2012a)

Carpenter syndrome

Jenkins et al. (2011)

Fukuda (2013), Ostrowski et al. (2010) Roosing et al. (2013)

Griscelli syndrome; choroideremia Autosomal-recessive cone-rod dystrophy

Menasche et al. (2000), Seabra et al., (1995) Roosing et al. (2013)

XLID associated with autism spectrum disorder, epilepsy, macrocephaly

Giannandrea et al. (2010)

Zuk and Elferink (2000) Mori et al. (2012)

Dejgaard et al. (2008) Ng et al. (2012, 2009), Ng and Tang (2008)

Nakazawa et al. (2012)

Giannandrea et al. (2010)

Rodriguez-Gabin et al. (2004)

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Function (brain specific)

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RABs

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Table 1 Reported RABs associated with CNS functions in health and disease.

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dissociation. Remarkably the structure of GDI includes a pocket for the hydrophobic prenyl groups that normally anchor RAB proteins to membranes. This membrane extraction process can retrieve RAB proteins from target membranes after a vesicular transport event. GDI–GDP–RAB prenylated dissociation is facilitated by membrane bound GDF (GDI displacement factors) (Barr and Lambright, 2010; Itzen and Goody, 2011). Heterodimeric RAB GEFs could also recruit subsequent acting RABs as part of a process called RAB cascade (Pfeffer, 2013). ␣GDI protein exerts a ubiquitous control on the retrieval of RABs proteins to the GDP bound state and can therefore have a broader impact on several RAB cascades across compartments (Pfeffer, 2013). See also Barnekow et al. (2009) for a broader discussion on compartmentalization of RAB GTPases.

The intracellular vesicle traffic and cargo delivery in neurons is defined by several events: cargo selection, budding, coating and scission of vesicles from their donor membrane, and then transport of vesicle along cytoskeleton structures, association of vesicles with the correct target membrane mediated by “tethering complexes” and finally the vesicle fusion through SNAREs complexes. During all these steps specific RAB GTPases contribute to define the correct and directional delivery of cargos between different compartments (e.g. from endoplasmic reticulum (ER) to Golgi cisternae) (Fukuda, 2008; Kennedy and Ehlers, 2006; Stenmark, 2009). Vesicle cargo selection is possibly the most important step in intracellular traffic and it is dependent on the components of the complexes coating the vesicles (COPI, COPII and clathrin). RAB GTPases main role is, at this point, the recruitment of the coat complexes and other effector proteins necessary for the vesicle formation. Several RAB effectors have BAR domains (Bin/Amphiphysin/RVS (BAR)), which are able to induce membrane curvature or sense them. For instance, RAB7 aids the recruitment of the retromer complex, which has been proposed to mediate the generation of trans Golgi network (TGN)bound vesicles from endosomes and to play a role in cargo sorting (Nakada-Tsukui et al., 2005; Seaman et al., 2009). RAB GTPases also control retrograde membrane trafficking to return escaped ER resident proteins and other machinery that cycles between the ER and Golgi back to their site of origin (Liu and Storrie, 2012). RAB2, for instance, works at the interface between the late Golgi apparatus and ER and requires glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and atypical protein kinase Ciota (aPKCiota) for retrograde vesicle formation from vesicular tubular clusters to sort secretory cargo from recycling proteins returned to the ER (Tisdale and Artalejo, 2006). These complex exchanges should be seen in the context of chains of molecular events (RAB cascades), which are affecting the direction of transport through the secretory and endocytic pathways for instance at different stages of neuronal maturation (Pfeffer, 2013; Sasidharan et al., 2012). RAB1 enzyme is localized in the ER where it controls cargo concentration of the neuronal glutamate transporter excitatory amino-acid carrier 1 (EAAC1) and it is specifically inhibited by another protein also ER-localized: GTRAP3, which is highly expressed only during early brain development until the start of synaptogenesis (Maier et al., 2009).

release of their content into the synaptic cleft. The recycling of SV and membranes by endocytosis ensures the refilling of SV storage. The first studies that concentrated on the SV release and recycling at the pre-synaptic site discovered that RAB3 subfamily was a major player (Fischer von Mollard et al., 1994a; Geppert et al., 1997; Gonzalez and Scheller, 1999). It has been reported by many laboratories that RAB3A controls docking and fusion events of SV at the presynaptic site interacting with several proteins, such as rabphilin, synapsin, Munc-13 and RIM (Castillo et al., 2002; Dulubova et al., 2005; Fischer von Mollard et al., 1990; Geppert et al., 1997; Pavlos et al., 2010; Schluter et al., 2002, 2004). Rabphilin is recruited to the surface of the SV by binding to RAB3A, while the interaction of RAB3A with RIM and Munc13 components of the active zone is part of the events that regulate secretion. Synapsins are RAB3A effector proteins that stimulate GTP binding and GTPase activity of both purified and endogenous SV-associated RAB3A. RAB3A associated with SV is decreased in synapsin-null mice, and the presence of synapsin I can prevent RAB-GDI-induced RAB3A dissociation from SV (Giovedi et al., 2004). Despite all this evidence for an important function of RAB3 family in SV fusion and neurotransmitter release, in the quadruple-null mice of all Rab3 (Rab3a, b, c, d) isoforms there was only a small decrease in SV exocytosis (about 30% decrease in evoked response). SV biogenesis, transport, docking and priming were not altered, indicating that RAB3 role is limited to the modulation of the SV release machinery (Schluter et al., 2004). Furthermore, rabphilin or RIM deletion in mouse resulted only in mild defects in exocytosis and did not affect RAB3A localization (Castillo et al., 2002; Schluter et al., 2004). Another protein involved in SV fusion and with a proposed overlapping role with RAB3A is RAB27B. In fact RAB27B expression seems to be restricted to the CNS and was found enriched on SVs (Pavlos et al., 2010; Zhao et al., 2002). Remarkably, RAB27B is localized on SV membranes during Ca2+ -triggered exocytosis, whereas RAB3A dissociates spontaneously. Recently, it is been proposed that RAB3A and RAB27B work together in the co-ordination of SV docking and fusion. In particular these two proteins would act in a RAB cascade, functioning in successive steps of SV release cycle. This hypothesis is supported by the observation that the two RABs share common interacting proteins (RIM, Munc-13) involved in docking and tethering of SVs. In particular, when RAB3A and RAB27B are associated with the SV and in their GTP-bound state, they would recruit all the molecular machinery (Rabphilin and Synaptotagmin family proteins for docking, RIMs and Munc-13 for priming) necessary for the steps of SV exocytosis. Upon exocytosis triggered by Ca2+ influxes and prior to fusion, RAB3A is inactivated by its GAP and extracted from the SV membrane by ␣GDI, while RAB27B remains in the SV membranes even during SNARE-mediated fusion process (Pavlos and Jahn, 2011). Endocytotic events are instead controlled by RAB8, RAB4, RAB5 and RAB11 (Fig. 2). These RAB GTPases are found on endosomes and also regulate different steps of the endocytic process at the level of the post-synapsis. The recent study of Tower-Gilchrist et al. (2011) reports real time observation on the transport of somatostatin receptor 3 through RAB4-, RAB21-, and RAB11-containing endosomes following this chain of events and highlighting a potentially specific role of RAB21 in the endosomal transport of newly synthesized G-protein coupled receptors while RAB5/RAB7/RAB11 interplay seems to control RGS4 internalization and recycling fate in the endosomal compartment (Bastin and Heximer, 2013).

3.2. Synaptic vesicles fusion and endocytosis

3.3. Axonal and dendritic transport

Quantal neurotransmission relies upon synaptic vesicles (SV) release by fast exocytosis when in the presence of an action potential. The local transient increase in Ca2+ concentration at the active zone triggers the fast and transient exocytosis of docked SV and the

In neurons RABs have important functions in axonal anterograde and retrograde transport. Of particular relevance for the purpose of this review is the control exerted by RABs on the anterograde transport of newly synthesized G-protein coupled receptors

3. RAB GTPases functions in neurons and astrocytes: from cargo recognition to receptor desensitization 3.1. ER–Golgi vesicle trafficking

Please cite this article in press as: D’Adamo, P., et al., RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2013.12.009

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target RAB5, in hippocampal neurons inhibited morphogenesis of both axons and dendrites, whereas knock down of RAB17 affected dendrite morphogenesis alone. Based on these findings, they propose that Rabex-5 regulates neurite morphogenesis of hippocampal neurons by activating at least two downstream targets, RAB5, which is localized in both axons and dendrites, and RAB17, which is localized in dendrites alone (Mori et al., 2013). Another recent study found RAB33A expression up-regulated during axon outgrowth in rat hippocampal neurons in culture. It has been suggested that RAB33A participates in axon outgrowth by mediating anterograde axonal transport of synaptophysin-positive vesicles and their fusion at the growth cones (Nakazawa et al., 2012). 3.5. Metabolic/trophic role of RABs in glial cells Fig. 2. SV exo-endocytotic cycle and the role of RAB GTPases. A different set of RAB GTPases is responsible for the fate of synaptic vesicles that partially or completely fuse with the presynaptic membrane at the active zone and fused vesicles that are retrieved by clathrin-mediated endocytosis. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.) Adapted from Shupliakov and Brodin (2010).

(GPCR) (Chen et al., 2012). One of the first studies on this topic demonstrated a role for RAB8 in dendrite-specific transport. Results indicated an involvement of RAB8 in transport of proteins to the dendritic surface in neurons caused by a dramatic reduction of vesicles undergoing anterograde transport because of a restriction of newly formed exocytic vesicles moving into the neurite in RAB8 depleted cells (Huber et al., 1993). Reports of a role of RAB21 and the relative GEF protein Varp in differentiating hippocampal neurons are somehow linking this RAB to the non-canonical SNARE VAMP7. This pathway may be affecting the transport of exocytotic vesicles to the cell periphery (Burgo et al., 2012). Specific paths of retrograde transport and constitutive internalization of receptors are also in the hands of specific RABs. RAB7 controls the retrograde axonal transport of nerve growth factor (NGF)-endosomes and neurotrophin receptors (Zhang et al., 2013). RAB7 and RAB5 mediate the fast retrograde transport of purinergic (P)2X3 (P2X3 ) receptors, while RAB5 controls the early sorting of P2X3 receptors into endosomes in primary sensory neurons, indicating a multiple role of the same RAB proteins in this pathway (Chen et al., 2012). 3.4. Neurite morphogenesis and outgrowth RABs have been associated with neurite morphogenesis and outgrowth, in particular RAB11, RAB17 and RAB33A. RAB11 (GDP bound) has been reported to enhance neurite growth through its interaction with protrudin. Phosphorylation of protrudin by extracellular signal-regulated kinase (ERK) in response to nerve growth factor promotes this association and down-regulation of protrudin by RNA interference induces membrane extension in all directions and inhibits neurite formation. Thus, protrudin regulates RAB11-dependent membrane recycling to promote the directional membrane trafficking required for neurite formation (Shirane and Nakayama, 2006). RAB17 has been shown to regulate dendritic morphogenesis of mouse hippocampal neurons and post-synaptic development (Mori et al., 2012). Recently, the discovery that Rabex5 and ALS2, originally described as RAB5-GEFs, are also RAB17-GEF elucidates the molecular mechanism of RAB17-mediated dendritogenesis. Mori et al. described that expression of Rabex-5, but not of ALS2, promotes translocation of RAB17 from the cell body to the dendrites of developing mouse hippocampal neurons. Knock down studies, by shRNA-mediated Rabex-5 or its known downstream

The specific roles of RAB GTPases in glial cells have not yet been deeply elucidated and little is known about their functions in the various glial cellular subtypes. RAB3 subfamily expression has been investigated and RAB3 isoforms are differentially expressed in glial cells. Oligodendrocytes have been reported to express RAB3A and RAB3C, whereas astrocytes express RAB3B (Madison et al., 1996). RAB40C was cloned from an oligodendrocytes cDNA library and, in HeLa cells, was found to localize in the perinuclear-recycling compartment. RAB40C transcripts are increased in mature oligodendrocytes suggesting a role in myelination (Mellman, 1996). Recent studies focused on RAB22B expression in glial cells. Thanks to specific antibodies, RAB22B expression was revealed in mouse embryonic brain where it localizes with nestin and RC2positive radial glial cells. In the adult brain RAB22B co-localized with GFAP-positive astrocytes but is not clearly detectable in mature oligodendrocytes or TuJ-positive neurons. Silencing of RAB22B in A431 cells resulted in abnormal trafficking of epidermal growth factor receptor (EGFR). It was therefore suggested that RAB22B is specifically expressed in the astroglia lineage and may have role in regulating EGFR trafficking (Anitei et al., 2009). More recently the role of RAB4 and RAB5 has been investigated in the direction mobility of endocytic vesicles in astrocytes. In astrocytes, vesicles have been shown to exhibit both non-directional and directional mobility, which can be intermittent. Astrocytes transfected with different GDP- and GTP-locked mutants of RAB4 and RAB5 showed a reduction of vesicles exhibiting directional mobility. These data suggested that a functional GTP–GDP switching is required for maintaining directional mobility and for the proper attachment of vesicles to motor and/or effector proteins and cytoskeleton elements (Potokar et al., 2012). 4. Brain expression of RAB GTPases The discrete brain expression profile of RABs remains poorly understood. Many RAB proteins are ubiquitously expressed while only few reports are devoted to the characterization of RAB GTPases, which have been shown to be brain-enriched, and with a documented role in neurons (Ng and Tang, 2008). Database search for mouse brain expressed RABs, at the BioGPS portal (http://biogps.org/#goto=welcome) based on Affymatrix gene expression data, report that, among the 58 RABs with expression data available, 18 are expressed predominantly in brain and among them 8 are highly brain enriched and 10 are brain specific (Table 2). This observation confirms that RAB GTPase cell specific function can be mainly related to the complexity of the specific subcellular system of interacting proteins, more than to a cell type specific RAB expression profile. Nevertheless more effort should be placed on the characterization of RAB15, RAB3C and RAB9B and

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BioGPS

Rab1a Rab2b Rab3a Rab3b Rab3c Rab4a Rab5a Rab6a Rab6b Rab9b Rab11a Rab11b Rab15 Rab26 Rab28 Rab33a Rab39b Rab40b

High High Specific Specific Specific High High High Specific Specific High High Specific Specific High Specific Specific Specific

their splice variants (Pham et al., 2012) as neuronally expressed GTPases with a potential role in neuronal development and differentiation. What is known is that RAB15 is responsible for transferrin receptor trafficking through sorting endosomes and the endocytic recycling compartment (Strick and Elferink, 2005), RAB3C is involved in a preferential interaction with ZW10-interaction protein 1 in hippocampal neurons pre-synapsis (van Vlijmen et al., 2008) and RAB9B should receive more attention potentially in the context of intellectual disability because of genetic studies (Torisu et al., 2012). 5. Developmental aspects of the biology of RAB GTPases in the central nervous system and deficits in neurodevelopmental disorders Neurite formation and neurite outgrowth are under tight developmental control in the human brain and given the relevance of RAB GTPases in this process, it may be important to look at the main transcriptional factors responsible for the expression of specific RAB GTPases in the CNS. These studies have so far defined p53 transcription factor as upstream Rab13 gene expression, which is required for neurite outgrowth (Ma et al., 2011; Quadrato and Di Giovanni, 2012). When it comes to the exocytotic pathway, the regulation was mainly studied in pancreatic ␤-cells but the results can be most likely extended to nervous tissue. Interestingly, a number of promoters of the genes coding for key components of the machinery of exocytosis; including promoters of RAB3A, RAB27A and of two of their effectors, granuphilin and Noc2 contain potential CREs (cAMP response elements) and might be regulated by transcription factors from the CREB (CRE-binding protein) and CREM (CRE modulator)/ICER families (Abderrahmani et al., 2006). Still unexplored is instead the role of microRNA families in the expression of different RABs (e.g. RAB27). The expression of specific RABs, on the other hand, is affecting key growth signalling pathways like EGFR pathway (for RAB7) and TGF␤ (for RAB5 and RAB11). The largest body of evidence of a role of RAB GTPases in brain development is coming from family genetic studies and null mutant mice. 5.1. X-linked forms of intellectual disability (XLID) Intellectual disability (ID), is a common neurodevelopmental disorder characterized by an IQ lower than 85. Family studies have demonstrated a relatively large number of X-linked forms (XLID) with an incidence of about 0.9–1.4 over 1000 males (Turner et al.,

1996). In recent years more than 90 different genes were identified (Chiurazzi et al., 2008; Lisik and Sieron, 2008; Ropers, 2008) encoding for proteins with a large variety of functions; i.e. chromatin remodelling, synaptic function, intracellular trafficking, etc. Thus, XLID represents the final phenotypic outcome of many different types of abnormal cellular processes leading to pre- and/or postsynaptic neuronal terminals dysfunction (Chiurazzi et al., 2008). A rare form of non-specific X-linked intellectual disability (XLID) is caused by a mutation in RAB GDP dissociation inhibitor ␣ (GDI1), one of two GDI isoforms in humans (D’Adamo et al., 1998). Because GDIs redundant functions, it is not easy to pinpoint which RAB GTPase is primarily affected by the dysfunction of GDI1. Mice lacking Gdi1 have impaired RAB GTPases recycling leading to an accumulation of their membrane-associated form on specific organelles. We demonstrated that this is the case for a number of RAB GTPases (D’Adamo et al., 2002) and we showed that lack of ␣GDI in mice impaired hippocampus dependent short-term memory formation and greatly reduced mouse male aggression, thereby modifying their social interaction (D’Adamo et al., 2002). 5.2. Autism spectrum disorders (ASD) Among the XLID genes identified until now, loss of function mutations in RAB39B lead to ID associated with ASD (Giannandrea et al., 2010; Vissers et al., 2010). We showed that RAB39B, a novel RAB GTPase of unknown function, is a neuronal-specific protein that localize to the Golgi compartment. Rab39b down regulation leads to an alteration in the number and morphology of neurite growth cones and a significant reduction in presynaptic buttons, suggesting that RAB39B is required for synapse formation and maintenance. ASD was also linked to a direct interruption of the RAB11 family interacting protein 5 (RAB11FIP5) gene. RAB11FIP5 is a RAB effector involved in protein trafficking from apical recycling endosomes to the apical plasma membrane (Roohi et al., 2008). 6. Deficit in RAB and RAB interacting proteins in human neurological diseases Both RABs and RAB-associated proteins have been shown to play an important role in a number of rare monogenic (Bem et al., 2011; Handley et al., 2013) as well as multifactorial neurological diseases (Corbeel and Freson, 2008) as summarized in Tables 1 and 3. It is interesting to note that these mutations occur not only in neuronal or CNS-specific RABs, but also in RABs that are ubiquitously expressed. The cell types most affected by such mutations are localized in the CNS, possibly because of specific functions or the main role played by recycling endosomes and Golgi-network in neurons. This is typically the case of RAB6 role in amyloid precursor protein endocytosis via Mint proteins (Chaufty et al., 2012; Teber et al., 2005). Golgi fragmentation is a common feature in in vitro models of different neurological disorders (e.g. alpha synuclein overexpression causes main disruption to RABs functions) and the cellular phenotype can be usually rescued by overexpression of different RAB GTPases as in the case of RAB7L1 overexpression that rescued the LRRK2 mutant phenotypes in a model of Parkinson’s disease (MacLeod et al., 2013). 7. RAB GTPases related mouse models: assessment of cognitive deficits 7.1. RAB3 family animal models Geppert et al. first generated Rab3a-null mice in 1994. Mice appeared viable and fertile and no changes were observed in brain

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Table 3 Reported RABs interacting proteins associated with CNS alterations. Effectors and interacting proteins

Associated RAB

Disease associated

Rab11FIP5 SH3TC2 ALS2/alsin Rab5 GEF RAb3GAP1,2

RAB11 RAB11 RAB5 RAB3A,B,C,D

Autism spectrum disorders (Roohi et al., 2008) Charcot–Marie–Tooth neuropathy (Stendel et al., 2010) Amyotrophic lateral sclerosis (Kenna et al., 2013) Warburg and Martsolf syndrome (Aligianis et al., 2005)

morphology, neural development and synaptic structure by light or electron microscopy, indicating that RAB3A is not fundamental for neuronal development. The size of excitatory postsynaptic currents (EPSCS) in hippocampal CA1 pyramidal cells upon stimulation of the Schaffer collateral-commissural fibres was not altered. In addition, other synaptic parameters, such as paired-pulse facilitation, post-tetanic potentiation and LTP were not affected by the absence of RAB3A. Only after short trains of repetitive stimulation (15–30 stimuli at 14 Hz), synaptic transmission in the mutant mice was significantly depressed. The authors therefore suggested that the Rab3a-null phenotype was dependent on a defect in SV docking, since the synaptic transmission was altered only after docked vesicles have been exhausted (Geppert et al., 1994). In addition it was observed that Rab3a-null mice show a 70% decrease in rabphilin (a RAB3A effector protein) level. The levels of many other synaptic proteins, including ␣GDI – known to bind RAB3A – were found not altered. In a later work of Geppert et al. (1997), further characterized Rab3a-null mice reported that the readily releasable pool of vesicles is normal in Rab3a-null mice, whereas the Ca2+ triggered fusion is altered in the absence of RAB3A. In another work it was shown that in hippocampal CA3 mossy fibre synapses LTP and LTD were abolished in Rab3a-null mutant mice (Castillo et al., 1997). Hensbroek et al. (2003) reported that spatial working memory was unchanged in these mice. These findings lead to the claim that mossy fibre LTD and LTP, found to be impaired in Rab3a-null mutant mice, are not necessary for hippocampus-depending learning. In addition we found that Rab3a-null mice showed normal acquisition but moderately impaired platform reversal learning both in reference and episodic-like memory water maze tasks. We were also able to observe a mild deficit in spatial working memory when mice were tested in radial maze. We also carried out an extensive analysis of explorative behaviour using different tests such open field, O-maze, dark/light box and novel object tests. These tests revealed an increased locomotor activity and enhanced exploratory activity in Rab3a-null mice, indicating a form of hyperactivity combined with reduced measures of fear and hyper-reactivity towards novel stimuli. Overall from these results, it appears that RAB3A is not involved in memory processing, but rather that might play a specific role in the reactivity to novel stimuli and behavioural stability (D’Adamo et al., 2004). In 2002, in a screen for mouse mutants with abnormal rest-activity and sleep patterns, identified a semidominant mutation (called earlybird) that shortens the circadian period of locomotor activity. The mutation was discovered to be a point mutation in the Rab3a gene, in particular in the sequence of the GTPbinding domain. The mutation resulted in significantly reduced levels of RAB3A protein (by approximately 73%) in mutant mice, however, it did not affect the expression of rabphilin, a RAB3A effector proteins, know to be reduced in Rab3a-null mice. Both earlybird mice, as well as mice null for one Rab3a allele, showed anomalies in circadian period and sleep homeostasis for reasons still unknown (Kapfhamer et al., 2002). More recently the role of RAB3B in synaptic transmission, memory formation and learning has been investigated. Tsetsenis et al. (2011) reported that RAB3B is enriched in inhibitory synapses of the CA1 region of the hippocampus, where it localizes predominantly with glutamic acid dehydrogenase 65 (GAD65), a marker for inhibitory GABAergic synapses. Acute brain slices recordings

of the amplitude and frequency of spontaneous miniature excitatory postsynaptic currents (mEPSC), of excitatory field potentials (fEPSP), of paired-pulse ratios (PPR), and of the amplitude and frequency of miniature inhibitory postsynaptic currents (mIPSCs) in Rab3b-null mice revealed that baseline transmission, presynaptic short-term plasticity, and postsynaptic LTP were normal. On the other hand, Rab3b-null mice showed impaired i-LTD, a presynaptic form of inhibitory LTD that depends on endocannabinoids and on the protein RIM1alfa (Chevaleyre et al., 2007; Tsetsenis et al., 2011). Given these findings, Rab3b-null mice have been further characterized in order to investigate possible behavioural phenotypes. Interestingly, Rab3b-null mice displayed a selective enhancement in reversal learning when tested in the cued version of Morris water maze and in fear-conditioning assays, suggesting that RAB3B’s contribution to i-LTD in the CA1 region of the hippocampus is important for the stability of acquired memories (Tsetsenis et al., 2011). Südhof et al. generated multiple null animals of the various RAB3 isoforms to better elucidate their molecular function. They found that all single and double null mice were viable and fertile; however, the deletion of three RAB3 proteins is lethal whenever RAB3A is one of the deleted proteins. On the other hand, triple null mice expressing RAB3A were viable and fertile. Quadruple null mice are born alive and initially develop normally, but they die shortly after, due to respiratory failure. Interestingly, the expression of a single wild type Rab3a allele in quadruple null mice was sufficient to reverse the lethality at birth. These data indicate that RAB3 proteins may be functionally redundant, despite their different localization. Interestingly, the structure and composition of Rab3-null mice brains did not reveal any obvious morphological alterations and/or developmental abnormalities. Out of 26 neuronal proteins, only rabphilin was found altered in Rab3-null mice. Synaptic transmission in quadruple null mice was studied in cultured hippocampal neurons and revealed that vesicle exocytosis showed a discrete impairment of release (30% decrease in evoked responses) that could be attributable to a decline in the synaptic and vesicular release probability. In addition the authors could not observe any significant impairment of SV biogenesis, transport, docking and priming. All together these data seem to suggest that RAB3 family is implicated in Ca2+ triggered SV exocytosis, but that it is not itself essential for synaptic membrane traffic. Therefore RAB3 family function is only to modulate the machinery of the release of SVs (Schluter et al., 2004). Null animal models have been also developed for RAB3 interacting proteins and it is interesting to note that their molecular and behavioural phenotype is not always similar to the one described for Rab3a-null mice or Rab3-null mice. Yamaguchi et al. generated rab3gef-null mice in 2002. They reported that these mice die immediately after birth because of respiratory failure. They also showed that the total number of SV in the neuromuscular junction of Rab3gef-null mice is strongly reduced compared with control mice, indicating an essential role for RAB3GEF in neurotransmitter release in the peripheral nervous system. Studies on hippocampal neurons from Rab3gef-null mice revealed a selective decrease in Ca2+ evoked response with normal size of the readily releasable pool, similarly to the phenotype observed in Rab3-null mice. Unlike in Rab3-null mice, Rab3gef-null

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mice show changes in the frequency of spontaneous miniature release events (Yamaguchi et al., 2002). Rabphilin-null animal model show no phenotype and RAB3A is targeted normally to the SV with no alteration in synaptic properties, indicating that rabphilin is not essential for the regulatory functions of RAB3A in synaptic transmission (Schluter et al., 1999). Rim1alfa-null mice show a severe phenotype partially overlapping with the one of Rab3-null mice (Calakos et al., 2004; Schoch et al., 2002). However, RIM1alfa deficient synapse shows a 50% decrease in the readily releasable pool, which is not the case for Rab3-null mutant mice synapses. ␣GDI is a regulator of RAB3A recycling (and of all other RAB GTPases) and in our laboratory we have extensively characterized this animal model. Electrophysiological analysis of Gdi1-null mice revealed alteration both in long- and short-term synaptic plasticity (D’Adamo et al., 2002; Ishizaki et al., 2000), which are different from those described for Rab3a-null mice. It is interesting to note that lack of ␣GDI does not alter the levels and the intracellular distribution of RAB3A and, conversely, the lack of RAB3A does not seem to alter ␣GDI protein expression. We have also compared the behavioural phenotype of Gdi1-null mice with the one of Rab3a-null mice using the same standardized tests and we did not find any phenotypic similarity between the two strains. Gdi1-null mice display impairment in associative memory, which could not be detected in Rab3a-null mice (D’Adamo et al., 2004). 7.2. Gdi1 mouse models and cognition ␣GDI-RAB proteins interact with pathways important for development of cognitive functions. The complete ablation of Gdi1 gives rise to a complex phenotype probably due to alterations in temporal and spatial functioning of ␣GDI and some of its associated RABs. The lack of ␣GDI in adult mice impairs hippocampus-dependent forms of short-term memory, spatial working memory and associative fear-related memory (D’Adamo et al., 2002). We generated also a conditional ␣CamKII-Gdi1flox/Y mouse to investigate the effects of Gdi1 deletion in specific brain areas and to examine the outcome of such deletion in an already developed CNS. This mouse showed similar cognitive deficits of the Gdi1-null mouse when tested in adulthood but with the presence of a stronger pre-synaptic impairment, suggesting that the temporal and spatial regulation of RABs in neurons by ␣GDI is important for the neuronal networking function at all stages of brain maturation and into adulthood (Bianchi et al., 2009, 2012; D’Adamo et al., 2002). A significant down-regulation of Gdi1 in this conditional mouse model starts after the end of the third postnatal week, i.e. when many of the CNS neuronal pathways have already been established (Bianchi et al., 2012). This probably explains the stronger phenotype since no early adaptation to a constitutive lack of ␣GDI can take place. Another strong piece of evidence on the fundamental role of ␣GDI in brain development was the impaired synaptic functioning in the constitutive Gdi1-null mouse model seen at post-natal day (PND) 28. We have observed a strong reduction in the overall synaptic weight at these synaptic contacts, associated with alterations of pre- but not postsynaptic parameters, that suggests specific alterations in the refilling rate of release sites (Bianchi et al., 2012). To understand if the effect of Gdi1-null mutation could be observed already in pre-juvenile mice we have carried out specific behavioural studies in young Gdi1-null male mice (Fig. 3 and Table 4). We investigated the Gdi1-null mouse model via a comprehensive set of paradigms spanning from sensorimotor responses of neonatal Gdi1-null mouse, exploratory behaviour in pre-juvenile Gdi1-null, and spatial working memory and associative learning in the juvenile mice. Our goal was to identify behavioural traits that could be used as reliable indicators of development of cognitive impairment (Bespalov et al., 2012; Klin et al., 2009). The Fox

battery was carried out from PND 3 to PND 18 and showed no deficits in sensorimotor responses of neonatal Gdi1-null mouse thus confirming the non-specific aspect of this model also in early age. In pre-Juvenile mice the emotional state assessed in the dark-light and emergence test, respectively, showed no difference between genotypes. Instead, the only behavioural feature reliably present in pre-juvenile animals was marked hyperactivity that disappeared with the adult life (Fig. 3A and B). Associative learning and working memory deficits appeared by PND 30 as we assessed by spontaneous alternation, hippocampus dependent spatial working memory task (Fig. 3C); the trace fear conditioning (TFC): a hippocampus dependent non-spatial task (Fig. 3D–F) and the contextual fear conditioning (CFC), which is an hippocampus independent learning task (Fig. 3G–I). By PND 30–32 mice show hippocampus dependent and hippocampus independent deficits while hyper-locomotion cannot be clearly seen and no double dissociation is possible since the poorer cognitive abilities may, theoretically, affect investigation (Sanderson et al., 2008). This hyperactive-behavioural pattern deserves further investigation as early trait potentially associated with development deficits. To explain the hippocampus-dependent memory deficit, we have analyzed in more detail hippocampal synapses. At the morphological level Gdi1-null mice display a 50% reduction in the total number of SVs in adult hippocampus. At the active zone, SVs appear normal, suggesting a defect of the SVs reserve pool. In order to evaluate the functional impact of the Gdi1 deletion on short-term plasticity at CA1 excitatory synapses of the hippocampus, we have analyzed paired-pulse facilitation (PPF), post-tetanic potentiation (PTP) and synaptic depression. Gdi1-null mice showed higher PPF, a stronger synaptic facilitation followed by a depressing phase similar to that observed in wild type animals but the subsequent recovery from depression was significantly delayed in Gdi1-null mice, suggesting an impaired SV recruitment possibly related to the marked reduction in the SV reserve pool. These data suggested that lack of ␣GDI alters steps controlling the formation and maintenance of the SV pools, hence interfering with the efficiency of mental processing. The hippocampus-related short-term memory deficit in Gdi1-null mice points towards defects in SVs recycling through significant alterations in the availability of RAB4, RAB5 and RAB11, the major RAB GTPases involved in endosomal trafficking and slow SV recycling (Bianchi et al., 2009) as well as RAB3A, the main RAB protein in synaptic vesicles, controlling SV exocytosis.

8. Perspective and potential therapeutic strategies Despite substantial progress on understanding the role played by RAB GTPases and their effector proteins on pathological mechanisms of cognitive disorders, no therapeutic intervention have been proposed until now. In line with what attempted for RAS and RHO GTPases (Pavlowsky et al., 2012), two strategies could be proposed based on both the knowledge obtained on RAB mechanistic role and target action on the final pathway impaired by the absence of these RAB/effector proteins. This is limited by the lack of wellcharacterized pre-clinical models that could offer the possibility to evaluate and validate a therapeutic approach. The assessment of the role of interacting proteins and in particular of Gdi1-null mutant mice has generated the best data so far on a role of RAB GTPases in cognition, also addressing some of the deficits observed in intellectual disability. The Gdi1-null mutant mice are still of main interest to study the presynaptic control on release machinery, to further clarify the circuitries most affected in intellectual disability and for potential pharmacological approaches. These mice could potentially be of use also to explore what really links the system of interacting proteins for each RAB since the relative expression

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Fig. 3. Behavioural assessment in pre- and juvenile Gdi1-null mice. Animals were maintained on a reversed 12 h light/darkness cycle and the room temperature was kept at 22–24 ◦ C. Food and water were available ab libitum in the home cage. All behavioural procedures were approved by the Department of Biotechnologies (DIBIT) Institutional Animal Care (Milan, Italy) and by the National Ministry of Health (IACUC #470). (A, B) Pre-juvenile (Gdi1-PJ) Gdi1-null mice show increased locomotor activity that disappears in adult life. Locomotor activity of Gdi1-null mice was assessed in two tests: the open-field (Tremml et al., 1998) and the emergence test (Madani et al., 2003). Gdi1-PJ Gdi1-null (n = 21) and Gdi1-control (n = 23) mice were compared with adult mice tested a PND 90 (Gdi1-A) both Gdi1-null (n = 16) and Gdi1 control (n = 15) mice. In the open-field (A), Gdi1-PJ null mice showed an increased locomotor activity. The distance travelled was 18% more than control animals; Gdi1-null 1.74 ± 0.08 and Gdi1-control 1.47 ± 0.07 m ± SE; genotype effect: F[1,42] = 4.67, p = 0.036. At PND 90 no difference was observed (Gdi1-A genotype effect: F[1,29] = 0.05, p = 0.83) as previously reported (D’Adamo et al., 2002). In the Emergence test (B), pre-juvenile Gdi1-null mice showed an increased locomotor activity when outside the box. The distance travelled was 12% more than control animals; Gdi1-null 2.42 ± 0.09 and Gdi1-control 2.16 ± 0.07 m ± SE; genotype effect: F[1,39] = 4.28, p = 0.031 (Fig. 1B). At PND 90 no difference was observed (Gdi1-A: genotype effect: F[1,29] = 0.39, p = 0.53) as previously reported (D’Adamo et al., 2002). (C) Both juvenile and adult Gdi1-null mice have impaired hippocampus dependent spatial working memory. Each mouse was singly in the central hub of a cross maze and let free to explore the maze for 10 min. The cross maze was obtained by leaving open 4 out of the 8 arms of a classical 8-radial arm maze for mice. Number and sequence of arm entries were recorded throughout the experiment. A correct alternation was considered when no more than one repetition over 5 entries was made (More et al., 2007; Ragozzino et al., 1996). The percentage of correct spontaneous alternations was statistical significant in both groups (Gdi1-J and Gdi1-A). Gdi1-J: Gdi1-control 72.85 ± 2.49% and Gdi1-null 58.47 ± 3.39% (two-tailed independent samples T-test, t[1,19] = 3.21; p < 0.005). Gdi1-A: Gdi1-control 70.34 ± 2.48% and Gdi1-null 52.89 ± 2.68% (two-tailed independent samples T-test, t[1,15] = 4.78; p < 0.001). (D, I) Juvenile Gdi1-null mice have impaired associative learning and memory assessed by two fear conditioning preparations. Auditory fear conditioning paradigms were employed to assess associative learning in Juvenile Gdi1-null and control mice, using contextual (CFC) (Phillips and LeDoux, 1992) or trace fear conditioning (TFC) (Huerta et al., 2000). In the CFC training phase (D, CS1-5: five tone conditioned stimuli) both genotypes showed similar associative learning over the conditioning session (genotype effect: F[1,20] = 0.33, p = 0.57) and no significant differences were observed between genotypes 24 h later for context memory (CTX) (genotype effect: F[1,20] = 2.28, p = 0.15, E). Instead, a significant difference was observed when animals were tested for the tone memory (BL: base line; CUE: tone presentation) (genotype effect: F[1,20] = 16.36, p = 0.0006, F). In the TFC training phase (G) Gdi1-null mice showed a significant lower freezing throughout the conditioning session compared to their littermates (genotype effect: F[1,18] = 12.15, p = 0.003). Significant differences between genotypes were observed when animals were tested for context memory (genotype effect: F[1,18] = 8.31, p = 0.009, H), but not for the tone memory (genotype effect: F[1,18] = 4.06, p = 0.06, I).

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Table 4 Procedures description and equivalent test-age in humans. Sample size (n)

Procedure

Procedure stage and age (PND)

Group

Age in humans (whole brain)

14 Gdi1-null 13 Gdi1-wt

Fox battery

Neo-natal to pre-juvenile (PJ)

PC 166, 211, 262, 318 (PND 48), 379 (PND 109), 445 (PND 175, 6 months)

21 Gdi1-null 23 Gdi1-wt

Light/dark Open field Emergence Light/dark Open field Emergence Spontaneous alternation CFC

Righting reflex (3, 6, 9, 12, 15, 18) Place response (3, 6, 9, 12, 15, 18) Grasp reflex (–, 6, 9, 12, 15, 18) Cross extensor refl. (3, 6, 9, 12, 15, 18) Postural flexion (3, 6, 9, 12, 15, 18) Cliff drop aversion (–, 6, 9, 12, 15, 18) Negative geotaxis (–, 6, 9, 12, 15, 18) (23) (24) (25) (90) (91) (92) Test (30)

Pre-juvenile (PJ)

Juvenile (J)

PC 568 (PND 298; 9.9 months) PC594 (PND 324; 10.8 months) PC 621 (PND 351; 11.7 months) >25 years >25 years >25 years PC 763 (PND 493; 16.4 months)

Test (32)

Juvenile (J)

16 Gdi1-null 15 Gdi1-wt 12 Gdi1-null 9 Gdi1-wt 11 Gdi1-null 9 Gdi1-wt 12 Gdi1-null 10 Gdi1-wt

TFC

seems to be almost unaffected by selectively knocking out one or more of these proteins. The best strategy is certainly to look at the overall complex of events rather than at a single RAB in isolation (with some exceptions), like suggested by several groups (Fukuda, 2010; Harris and Littleton, 2011). There is also an obvious need for a more systematic characterization of the role of CNS expressed RAB GTPases and their interacting proteins and to address specifically what happens during brain development and maturation. Small mammals and even invertebrate models could be of potential help, but the RAB GTPase system seems to have evolved following the specific needs of the human CNS and therefore more human genetic work would help to establish solid maps with further links to human brain development disorders like Intellectual Disability and Autism Spectrum Disorders. Last but not least there is still a technology call to image RABs functions, map expression profile and develop antibodies (whenever possible). The study of RAB family of GTPases is opening a window on the dynamics that constantly shape and reshape the CNS. To grasp the key elements of this complex series of events may bring a different level of understanding on what controls the development and the plasticity of cognitive functions. Acknowledgements Experimental studies were supported by “Comitato Telethon Fondazione Onlus” TCP04015 to P.D. and “F. Hoffmann La Roche post-doc program” RPF-138 to M.G. Authors thank R. Cassinari and A. Gamper for graphic support and F. Fanelli for RAB protein structure (Fig. 1). References Abderrahmani, A., Plaisance, V., Lovis, P., Regazzi, R., 2006. Mechanisms controlling the expression of the components of the exocytotic apparatus under physiological and pathological conditions. Biochem Soc Trans 34, 696–700. Aligianis, I.A., Johnson, C.A., Gissen, P., Chen, D., Hampshire, D., Hoffmann, K., Maina, E.N., Morgan, N.V., Tee, L., Morton, J., Ainsworth, J.R., Horn, D., Rosser, E., Cole, T.R., Stolte-Dijkstra, I., Fieggen, K., Clayton-Smith, J., Megarbane, A., Shield, J.P., Newbury-Ecob, R., Dobyns, W.B., Graham Jr., J.M., Kjaer, K.W., Warburg, M., Bond, J., Trembath, R.C., Harris, L.W., Takai, Y., Mundlos, S., Tannahill, D., Woods, C.G., Maher, E.R., 2005. Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nature genetics 37, 221–223. Allan, B.B., Moyer, B.D., Balch, W.E., 2000. Rab1 recruitment of p115 into a cis-SNARE complex: programming budding COPII vesicles for fusion. Science 289, 444–448. Anitei, M., Cowan, A.E., Pfeiffer, S.E., Bansal, R., 2009. Role for Rab3a in oligodendrocyte morphological differentiation. J Neurosci Res 87, 342–352. Barnekow, A., Thyrock, A., Kessler, D., 2009. Chapter 5: rab proteins and their interaction partners. Int Rev Cell Mol Biol 274, 235–274.

Adult (A)

PC 763 (PND 493; 16.4 months) PC 794 (PND 524; 17.5 months) PC 824 (PND 554; 18.5 months)

Barr, F., Lambright, D.G., 2010. Rab GEFs and GAPs. Curr Opin Cell Biol 22, 461–470. Bastin, G., Heximer, S.P., 2013. Rab Family Proteins Regulate the Endosomal Trafficking and Function of RGS4. J Biol Chem 288, 21836–21849. BasuRay, S., Mukherjee, S., Romero, E.G., Seaman, M.N., Wandinger-Ness, A., 2013. Rab7 mutants associated with Charcot-Marie-Tooth disease cause delayed growth factor receptor transport and altered endosomal and nuclear signaling. J Biol Chem 288, 1135–1149. Bem, D., Yoshimura, S., Nunes-Bastos, R., Bond, F.C., Kurian, M.A., Rahman, F., Handley, M.T., Hadzhiev, Y., Masood, I., Straatman-Iwanowska, A.A., Cullinane, A.R., McNeill, A., Pasha, S.S., Kirby, G.A., Foster, K., Ahmed, Z., Morton, J.E., Williams, D., Graham, J.M., Dobyns, W.B., Burglen, L., Ainsworth, J.R., Gissen, P., Muller, F., Maher, E.R., Barr, F.A., Aligianis, I.A., 2011. Loss-of-function mutations in RAB18 cause Warburg micro syndrome. American journal of human genetics 88, 499–507. Bespalov, A., Klein, C., Behl, B., Gross, G., Schoemaker, H., 2012. Development of disease-modifying treatment of schizophrenia. Handb Exp Pharmacol, 419–442. Bianchi, V., Farisello, P., Baldelli, P., Meskenaite, V., Milanese, M., Vecellio, M., Muhlemann, S., Lipp, H.P., Bonanno, G., Benfenati, F., Toniolo, D., D’Adamo, P., 2009. Cognitive impairment in Gdi1-deficient mice is associated with altered synaptic vesicle pools and short-term synaptic plasticity, and can be corrected by appropriate learning training. Hum Mol Genet 18, 105–117. Bianchi, V., Gambino, F., Muzio, L., Toniolo, D., Humeau, Y., D’Adamo, P., 2012. Forebrain deletion of alphaGDI in adult mice worsens the pre-synaptic deficit at cortico-lateral amygdala synaptic connections. PLoS One 7, e29763. Bienvenu, T., des Portes, V., Saint Martin, A., McDonell, N., Billuart, P., Carrie, A., Vinet, M.C., Couvert, P., Toniolo, D., Ropers, H.H., Moraine, C., van Bokhoven, H., Fryns, J.P., Kahn, A., Beldjord, C., Chelly, J., 1998. Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor. Hum Mol Genet 7, 1311–1315. Borck, G., Wunram, H., Steiert, A., Volk, A.E., Korber, F., Roters, S., Herkenrath, P., Wollnik, B., Morris-Rosendahl, D.J., Kubisch, C., 2011. A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. Hum Genet 129, 45–50. Brown, T.C., Correia, S.S., Petrok, C.N., Esteban, J.A., 2007. Functional compartmentalization of endosomal trafficking for the synaptic delivery of AMPA receptors during long-term potentiation. J Neurosci 27, 13311–13315. Brown, T.C., Tran, I.C., Backos, D.S., Esteban, J.A., 2005. NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 45, 81–94. Bucci, C., Parton, R.G., Mather, I.H., Stunnenberg, H., Simons, K., Hoflack, B., Zerial, M., 1992. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 70, 715–728. Burgo, A., Proux-Gillardeaux, V., Sotirakis, E., Bun, P., Casano, A., Verraes, A., Liem, R.K., Formstecher, E., Coppey-Moisan, M., Galli, T., 2012. A molecular network for the transport of the TI-VAMP/VAMP7 vesicles from cell center to periphery. Dev Cell 23, 166–180. Calakos, N., Schoch, S., Sudhof, T.C., Malenka, R.C., 2004. Multiple roles for the active zone protein RIM1alpha in late stages of neurotransmitter release. Neuron 42, 889–896. Castillo, P.E., Janz, R., Sudhof, T.C., Tzounopoulos, T., Malenka, R.C., Nicoll, R.A., 1997. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature 388, 590–593. Castillo, P.E., Schoch, S., Schmitz, F., Sudhof, T.C., Malenka, R.C., 2002. RIM1alpha is required for presynaptic long-term potentiation. Nature 415, 327–330. Chaufty, J., Sullivan, S.E., Ho, A., 2012. Intracellular amyloid precursor protein sorting and amyloid-beta secretion are regulated by Src-mediated phosphorylation of Mint2. J Neurosci 32, 9613–9625. Chen, R.H., Wislet-Gendebien, S., Samuel, F., Visanji, N.P., Zhang, G., Marsilio, D., Langman, T., Fraser, P.E., Tandon, A., 2013. alpha-Synuclein membrane

Please cite this article in press as: D’Adamo, P., et al., RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2013.12.009

G Model NBR-1879; No. of Pages 13

ARTICLE IN PRESS P. D’Adamo et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx

association is regulated by the Rab3a recycling machinery and presynaptic activity. J Biol Chem 288, 7438–7449. Chen, W., Feng, Y., Chen, D., Wandinger-Ness, A., 1998. Rab11 is required for transgolgi network-to-plasma membrane transport and a preferential target for GDP dissociation inhibitor. Mol Biol Cell 9, 3241–3257. Chen, X.Q., Wang, B., Wu, C., Pan, J., Yuan, B., Su, Y.Y., Jiang, X.Y., Zhang, X., Bao, L., 2012. Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons. Cell Res 22, 677–696. Cherfils, J., Zeghouf, M., 2013. Regulation of small GTPases by GEFs. GAPs, and GDIs. Physiol Rev 93, 269–309. Chevaleyre, V., Heifets, B.D., Kaeser, P.S., Sudhof, T.C., Castillo, P.E., 2007. Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha. Neuron 54, 801–812. Chi, Z.L., Akahori, M., Obazawa, M., Minami, M., Noda, T., Nakaya, N., Tomarev, S., Kawase, K., Yamamoto, T., Noda, S., Sasaoka, M., Shimazaki, A., Takada, Y., Iwata, T., 2010. Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice. Hum Mol Genet 19, 2606–2615. Chiurazzi, P., Schwartz, C.E., Gecz, J., Neri, G., 2008. XLMR genes: update 2007. Eur J Hum Genet 16, 422–434. Choudhury, A., Dominguez, M., Puri, V., Sharma, D.K., Narita, K., Wheatley, C.L., Marks, D.L., Pagano, R.E., 2002. Rab proteins mediate Golgi transport of caveolainternalized glycosphingolipids and correct lipid trafficking in Niemann-Pick C cells. J Clin Invest 109, 1541–1550. Cogli, L., Progida, C., Thomas, C.L., Spencer-Dene, B., Donno, C., Schiavo, G., Bucci, C., 2013. Charcot-Marie-Tooth type 2B disease-causing RAB7A mutant proteins show altered interaction with the neuronal intermediate filament peripherin. Acta Neuropathol 125, 257–272. Cooper, A.A., Gitler, A.D., Cashikar, A., Haynes, C.M., Hill, K.J., Bhullar, B., Liu, K., Xu, K., Strathearn, K.E., Liu, F., Cao, S., Caldwell, K.A., Caldwell, G.A., Marsischky, G., Kolodner, R.D., Labaer, J., Rochet, J.C., Bonini, N.M., Lindquist, S., 2006. Alphasynuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313, 324–328. Corbeel, L., Freson, K., 2008. Rab proteins and Rab-associated proteins: major actors in the mechanism of protein-trafficking disorders. Eur J Pediatr 167, 723–729. D’Adamo, P., Menegon, A., Lo Nigro, C., Grasso, M., Gulisano, M., Tamanini, F., Bienvenu, T., Gedeon, A.K., Oostra, B., Wu, S.K., Tandon, A., Valtorta, F., Balch, W.E., Chelly, J., Toniolo, D., 1998. Mutations in GDI1 are responsible for X-linked nonspecific mental retardation. Nature genetics 19, 134–139. D’Adamo, P., Welzl, H., Papadimitriou, S., Raffaele di Barletta, M., Tiveron, C., Tatangelo, L., Pozzi, L., Chapman, P.F., Knevett, S.G., Ramsay, M.F., Valtorta, F., Leoni, C., Menegon, A., Wolfer, D.P., Lipp, H.P., Toniolo, D., 2002. Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice. Hum Mol Genet 11, 2567–2580. D’Adamo, P., Wolfer, D.P., Kopp, C., Tobler, I., Toniolo, D., Lipp, H.P., 2004. Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1. Eur J Neurosci 19, 1895–1905. Dalfo, E., Gomez-Isla, T., Rosa, J.L., Nieto Bodelon, M., Cuadrado Tejedor, M., Barrachina, M., Ambrosio, S., Ferrer, I., 2004. Abnormal alpha-synuclein interactions with Rab proteins in alpha-synuclein A30P transgenic mice. J Neuropathol Exp Neurol 63, 302–313. Darchen, F., Goud, B., 2000. Multiple aspects of Rab protein action in the secretory pathway: focus on Rab3 and Rab6. Biochimie 82, 375–384. Deinhardt, K., Salinas, S., Verastegui, C., Watson, R., Worth, D., Hanrahan, S., Bucci, C., Schiavo, G., 2006. Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52, 293–305. Dejgaard, S.Y., Murshid, A., Erman, A., Kizilay, O., Verbich, D., Lodge, R., Dejgaard, K., Ly-Hartig, T.B., Pepperkok, R., Simpson, J.C., Presley, J.F., 2008. Rab18 and Rab43 have key roles in ER-Golgi trafficking. J Cell Sci 121, 2768–2781. del Toro, D., Alberch, J., Lazaro-Dieguez, F., Martin-Ibanez, R., Xifro, X., Egea, G., Canals, J.M., 2009. Mutant huntingtin impairs post-Golgi trafficking to lysosomes by delocalizing optineurin/Rab8 complex from the Golgi apparatus. Mol Biol Cell 20, 1478–1492. Deretic, D., Huber, L.A., Ransom, N., Mancini, M., Simons, K., Papermaster, D.S., 1995. rab8 in retinal photoreceptors may participate in rhodopsin transport and in rod outer segment disk morphogenesis. J Cell Sci 108 (Pt 1), 215–224. Dulubova, I., Lou, X., Lu, J., Huryeva, I., Alam, A., Schneggenburger, R., Sudhof, T.C., Rizo, J., 2005. A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity? Embo J 24, 2839–2850. Eggenschwiler, J.T., Bulgakov, O.V., Qin, J., Li, T., Anderson, K.V., 2006. Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins. Dev Biol 290, 1–12. Eggenschwiler, J.T., Espinoza, E., Anderson, K.V., 2001. Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412, 194–198. Elfrink, H.L., Zwart, R., Cavanillas, M.L., Schindler, A.J., Baas, F., Scheper, W., 2012. Rab6 is a modulator of the unfolded protein response: implications for Alzheimer’s disease. J Alzheimers Dis 28, 917–929. Elias, M., 2010. Patterns and processes in the evolution of the eukaryotic endomembrane system. Mol Membr Biol 27, 469–489. Esseltine, J.L., Ribeiro, F.M., Ferguson, S.S., 2012. Rab8 modulates metabotropic glutamate receptor subtype 1 intracellular trafficking and signaling in a protein kinase C-dependent manner. J Neurosci 32, 16933–16942.

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Fischer von Mollard, G., Mignery, G.A., Baumert, M., Perin, M.S., Hanson, T.J., Burger, P.M., Jahn, R., Sudhof, T.C., 1990. rab3 is a small GTP-binding protein exclusively localized to synaptic vesicles. Proc Natl Acad Sci U S A 87, 1988–1992. Fischer von Mollard, G., Stahl, B., Li, C., Sudhof, T.C., Jahn, R., 1994a. Rab proteins in regulated exocytosis. Trends Biochem Sci 19, 164–168. Fischer von Mollard, G., Stahl, B., Walch-Solimena, C., Takei, K., Daniels, L., Khoklatchev, A., De Camilli, P., Sudhof, T.C., Jahn, R., 1994b. Localization of Rab5 to synaptic vesicles identifies endosomal intermediate in synaptic vesicle recycling pathway. Eur J Cell Biol 65, 319–326. Frasa, M.A., Koessmeier, K.T., Ahmadian, M.R., Braga, V.M., 2012. Illuminating the functional and structural repertoire of human TBC/RABGAPs. Nat Rev Mol Cell Biol 13, 67–73. Fukuda, M., 2008. Regulation of secretory vesicle traffic by Rab small GTPases. Cell Mol Life Sci 65, 2801–2813. Fukuda, M., 2010. How can mammalian Rab small GTPases be comprehensively analyzed?: Development of new tools to comprehensively analyze mammalian Rabs in membrane traffic. Histol Histopathol 25, 1473–1480. Fukuda, M., 2011. TBC proteins: GAPs for mammalian small GTPase Rab? Biosci Rep 31, 159–168. Fukuda, M., 2013. Rab27 effectors, pleiotropic regulators in secretory pathways. Traffic 14, 949–963. Ganley, I.G., Carroll, K., Bittova, L., Pfeffer, S., 2004. Rab9 GTPase regulates late endosome size and requires effector interaction for its stability. Mol Biol Cell 15, 5420–5430. Geppert, M., Bolshakov, V.Y., Siegelbaum, S.A., Takei, K., De Camilli, P., Hammer, R.E., Sudhof, T.C., 1994. The role of Rab3A in neurotransmitter release. Nature 369, 493–497. Geppert, M., Goda, Y., Stevens, C.F., Sudhof, T.C., 1997. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature 387, 810–814. Gerges, N.Z., Backos, D.S., Esteban, J.A., 2004. Local control of AMPA receptor trafficking at the postsynaptic terminal by a small GTPase of the Rab family. J Biol Chem 279, 43870–43878. Gerges, N.Z., Brown, T.C., Correia, S.S., Esteban, J.A., 2005. Analysis of Rab protein function in neurotransmitter receptor trafficking at hippocampal synapses. Methods Enzymol 403, 153–166. Giannandrea, M., Bianchi, V., Mignogna, M.L., Sirri, A., Carrabino, S., D’Elia, E., Vecellio, M., Russo, S., Cogliati, F., Larizza, L., Ropers, H.H., Tzschach, A., Kalscheuer, V., Oehl-Jaschkowitz, B., Skinner, C., Schwartz, C.E., Gecz, J., Van Esch, H., Raynaud, M., Chelly, J., de Brouwer, A.P., Toniolo, D., D’Adamo, P., 2010. Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. American journal of human genetics 86, 185–195. Ginsberg, S.D., Mufson, E.J., Alldred, M.J., Counts, S.E., Wuu, J., Nixon, R.A., Che, S., 2011. Upregulation of select rab GTPases in cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer’s disease. J Chem Neuroanat 42, 102–110. Giovedi, S., Darchen, F., Valtorta, F., Greengard, P., Benfenati, F., 2004. Synapsin is a novel Rab3 effector protein on small synaptic vesicles. II. Functional effects of the Rab3A-synapsin I interaction. J Biol Chem 279, 43769–43779. Gitler, A.D., Bevis, B.J., Shorter, J., Strathearn, K.E., Hamamichi, S., Su, L.J., Caldwell, K.A., Caldwell, G.A., Rochet, J.C., McCaffery, J.M., Barlowe, C., Lindquist, S., 2008. The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci U S A 105, 145–150. Gonzalez Jr., L., Scheller, R.H., 1999. Regulation of membrane trafficking: structural insights from a Rab/effector complex. Cell 96, 755–758. Gutierrez, M.G., Munafo, D.B., Beron, W., Colombo, M.I., 2004. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci 117, 2687–2697. Handley, M.T., Morris-Rosendahl, D.J., Brown, S., Macdonald, F., Hardy, C., Bem, D., Carpanini, S.M., Borck, G., Martorell, L., Izzi, C., Faravelli, F., Accorsi, P., Pinelli, L., Basel-Vanagaite, L., Peretz, G., Abdel-Salam, G.M., Zaki, M.S., Jansen, A., Mowat, D., Glass, I., Stewart, H., Mancini, G., Lederer, D., Roscioli, T., Giuliano, F., Plomp, A.S., Rolfs, A., Graham, J.M., Seemanova, E., Poo, P., Garcia-Cazorla, A., Edery, P., Jackson, I.J., Maher, E.R., Aligianis, I.A., 2013. Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome. Hum. Mutat. 34, 686–696. Harris, K.P., Littleton, J.T., 2011. Vesicle trafficking: a Rab family profile. Curr. Biol. 21, R841–R843. Hensbroek, R.A., Kamal, A., Baars, A.M., Verhage, M., Spruijt, B.M., 2003. Spatial, contextual and working memory are not affected by the absence of mossy fiber long-term potentiation and depression. Behav. Brain Res. 138, 215–223. Hernandez-Hernandez, O., Guiraud-Dogan, C., Sicot, G., Huguet, A., Luilier, S., Steidl, E., Saenger, S., Marciniak, E., Obriot, H., Chevarin, C., Nicole, A., Revillod, L., Charizanis, K., Lee, K.Y., Suzuki, Y., Kimura, T., Matsuura, T., Cisneros, B., Swanson, M.S., Trovero, F., Buisson, B., Bizot, J.C., Hamon, M., Humez, S., Bassez, G., Metzger, F., Buee, L., Munnich, A., Sergeant, N., Gourdon, G., Gomes-Pereira, M., 2013. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour. Brain 136, 957–970. Houlden, H., King, R.H., Muddle, J.R., Warner, T.T., Reilly, M.M., Orrell, R.W., Ginsberg, L., 2004. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann Neurol 56, 586–590. Huber, L.A., Dupree, P., Dotti, C.G., 1995. A deficiency of the small GTPase rab8 inhibits membrane traffic in developing neurons. Mol Cell Biol 15, 918–924. Huber, L.A., Pimplikar, S., Parton, R.G., Virta, H., Zerial, M., Simons, K., 1993. Rab8, a small GTPase involved in vesicular traffic between the TGN and the basolateral plasma membrane. J. Cell Biol. 123, 35–45.

Please cite this article in press as: D’Adamo, P., et al., RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2013.12.009

G Model NBR-1879; No. of Pages 13 12

ARTICLE IN PRESS P. D’Adamo et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx

Huerta, P.T., Sun, L.D., Wilson, M.A., Tonegawa, S., 2000. Formation of temporal memory requires NMDA receptors within CA1 pyramidal neurons. Neuron 25, 473–480. Ishizaki, H., Miyoshi, J., Kamiya, H., Togawa, A., Tanaka, M., Sasaki, T., Endo, K., Mizoguchi, A., Ozawa, S., Takai, Y., 2000. Role of rab GDP dissociation inhibitor alpha in regulating plasticity of hippocampal neurotransmission. Proc. Natl. Acad. Sci. U.S.A. 97, 11587–11592. Itzen, A., Goody, R.S., 2011. GTPases involved in vesicular trafficking: structures and mechanisms. Semin. Cell Dev. Biol. 22, 48–56. Jenkins, D., Baynam, G., De Catte, L., Elcioglu, N., Gabbett, M.T., Hudgins, L., Hurst, J.A., Jehee, F.S., Oley, C., Wilkie, A.O., 2011. Carpenter syndrome: extended RAB23 mutation spectrum and analysis of nonsense-mediated mRNA decay. Hum Mutat 32, E2069–2078. Kapfhamer, D., Valladares, O., Sun, Y., Nolan, P.M., Rux, J.J., Arnold, S.E., Veasey, S.C., Bucan, M., 2002. Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse. Nat. Genet. 32, 290–295. Kenna, K.P., McLaughlin, R.L., Byrne, S., Elamin, M., Heverin, M., Kenny, E.M., Cormican, P., Morris, D.W., Donaghy, C.G., Bradley, D.G., Hardiman, O., 2013. Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing. J Med Genet 50, 776–783. Kennedy, M.J., Ehlers, M.D., 2006. Organelles and trafficking machinery for postsynaptic plasticity. Annu. Rev. Neurosci. 29, 325–362. Khvotchev, M.V., Ren, M., Takamori, S., Jahn, R., Sudhof, T.C., 2003. Divergent functions of neuronal Rab11b in Ca2+-regulated versus constitutive exocytosis. J Neurosci 23, 10531–10539. Klin, A., Lin, D.J., Gorrindo, P., Ramsay, G., Jones, W., 2009. Two-year-olds with autism orient to non-social contingencies rather than biological motion. Nature 459, 257–261. Lai, C., Xie, C., Shim, H., Chandran, J., Howell, B.W., Cai, H., 2009. Regulation of endosomal motility and degradation by amyotrophic lateral sclerosis 2/alsin. Mol Brain 2, 23. Li, C., Fan, Y., Lan, T.H., Lambert, N.A., Wu, G., 2012a. Rab26 modulates the cell surface transport of alpha2-adrenergic receptors from the Golgi. J Biol Chem 287, 42784–42794. Li, X., Sapp, E., Chase, K., Comer-Tierney, L.A., Masso, N., Alexander, J., Reeves, P., Kegel, K.B., Valencia, A., Esteves, M., Aronin, N., Difiglia, M., 2009. Disruption of Rab11 activity in a knock-in mouse model of Huntington’s disease. Neurobiol Dis 36, 374–383. Li, X., Valencia, A., McClory, H., Sapp, E., Kegel, K.B., Difiglia, M., 2012b. Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington’s disease mice. Biochem Biophys Res Commun 421, 727–730. Lisik, M.Z., Sieron, A.L., 2008. X-linked mental retardation. Med. Sci. Monit. 14, RA221–RA229. Liu, S., Storrie, B., 2012. Are Rab proteins the link between Golgi organization and membrane trafficking? Cell. Mol. Life Sci. 69, 4093–4106. Lombardi, D., Soldati, T., Riederer, M.A., Goda, Y., Zerial, M., Pfeffer, S.R., 1993. Rab9 functions in transport between late endosomes and the trans Golgi network. Embo J 12, 677–682. Luiro, K., Yliannala, K., Ahtiainen, L., Maunu, H., Jarvela, I., Kyttala, A., Jalanko, A., 2004. Interconnections of CLN3. Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway. Hum Mol Genet 13, 3017–3027. Ma, X., Fei, E., Fu, C., Ren, H., Wang, G., 2011. Dysbindin-1, a schizophrenia-related protein, facilitates neurite outgrowth by promoting the transcriptional activity of p53. Mol. Psychiatry 16, 1105–1116. MacLeod, D.A., Rhinn, H., Kuwahara, T., Zolin, A., Di Paolo, G., McCabe, B.D., Marder, K.S., Honig, L.S., Clark, L.N., Small, S.A., Abeliovich, A., 2013. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron 77, 425–439. Madani, R., Kozlov, S., Akhmedov, A., Cinelli, P., Kinter, J., Lipp, H.P., Sonderegger, P., Wolfer, D.P., 2003. Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin. Mol. Cell. Neurosci. 23, 473–494. Madison, D.L., Kruger, W.H., Kim, T., Pfeiffer, S.E., 1996. Differential expression of rab3 isoforms in oligodendrocytes and astrocytes. J. Neurosci. Res. 45, 258–268. Maier, S., Reiterer, V., Ruggiero, A.M., Rothstein, J.D., Thomas, S., Dahm, R., Sitte, H.H., Farhan, H., 2009. GTRAP 3-18 serves as a negative regulator of Rab1 in protein transport and neuronal differentiation. J. Cell. Mol. Med. 13, 114–124. Martelli, A.M., Baldini, G., Tabellini, G., Koticha, D., Bareggi, R., 2000. Rab3A and Rab3D control the total granule number and the fraction of granules docked at the plasma membrane in PC12 cells. Traffic 1, 976–986. Meggouh, F., Bienfait, H.M., Weterman, M.A., de Visser, M., Baas, F., 2006. CharcotMarie-Tooth disease due to a de novo mutation of the RAB7 gene. Neurology 67, 1476–1478. Mellman, I., 1996. Endocytosis and molecular sorting. Annu. Rev. Cell Dev. Biol. 12, 575–625. Menasche, G., Pastural, E., Feldmann, J., Certain, S., Ersoy, F., Dupuis, S., Wulffraat, N., Bianchi, D., Fischer, A., Le Deist, F., de Saint Basile, G., 2000. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nature genetics 25, 173–176. Mohrmann, K., Gerez, L., Oorschot, V., Klumperman, J., van der Sluijs, P., 2002. Rab4 function in membrane recycling from early endosomes depends on a membrane to cytoplasm cycle. J Biol Chem 277, 32029–32035. More, L., Gravius, A., Pietraszek, M., Belozertseva, I., Malyshkin, A., Shekunova, E., Barberi, C., Schaefer, D., Schmidt, W.J., Danysz, W., 2007. Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition. Behav. Pharmacol. 18, 273–281.

Mori, Y., Matsui, T., Fukuda, M., 2013. Rabex-5 protein regulates dendritic localization of small GTPase Rab17 and neurite morphogenesis in hippocampal neurons. J. Biol. Chem. 288, 9835–9847. Mori, Y., Matsui, T., Furutani, Y., Yoshihara, Y., Fukuda, M., 2012. Small GTPase Rab17 regulates dendritic morphogenesis and postsynaptic development of hippocampal neurons. J. Biol. Chem. 287, 8963–8973. Moritz, O.L., Tam, B.M., Hurd, L.L., Peranen, J., Deretic, D., Papermaster, D.S., 2001. Mutant rab8 Impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods. Mol Biol Cell 12, 2341–2351. Morton, A.J., Faull, R.L., Edwardson, J.M., 2001. Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease. Brain Res Bull 56, 111–117. Nakada-Tsukui, K., Saito-Nakano, Y., Ali, V., Nozaki, T., 2005. A retromerlike complex is a novel Rab7 effector that is involved in the transport of the virulence factor cysteine protease in the enteric protozoan parasite Entamoeba histolytica. Mol. Biol. Cell 16, 5294–5303. Nakazawa, H., Sada, T., Toriyama, M., Tago, K., Sugiura, T., Fukuda, M., Inagaki, N., 2012. Rab33a mediates anterograde vesicular transport for membrane exocytosis and axon outgrowth. J. Neurosci. 32, 12712–12725. Ng, E.L., Tang, B.L., 2008. Rab GTPases and their roles in brain neurons and glia. Brain Res. Rev. 58, 236–246. Pavlos, N.J., Gronborg, M., Riedel, D., Chua, J.J., Boyken, J., Kloepper, T.H., Urlaub, H., Rizzoli, S.O., Jahn, R., 2010. Quantitative analysis of synaptic vesicle Rabs uncovers distinct yet overlapping roles for Rab3a and Rab27b in Ca2+-triggered exocytosis. J. Neurosci. 30, 13441–13453. Pavlos, N.J., Jahn, R., 2011. Distinct yet overlapping roles of Rab GTPases on synaptic vesicles. Small GTPases 2, 77–81. Pavlowsky, A., Chelly, J., Billuart, P., 2012. Emerging major synaptic signaling pathways involved in intellectual disability. Mol. Psychiatry 17, 682–693. Pereira-Leal, J.B., Seabra, M.C., 2001. Evolution of the Rab family of small GTP-binding proteins. J. Mol. Biol. 313, 889–901. Pfeffer, S.R., 2013. Rab GTPase regulation of membrane identity. Curr. Opin. Cell Biol. 25, 414–419. Pham, T.V., Hartomo, T.B., Lee, M.J., Hasegawa, D., Ishida, T., Kawasaki, K., Kosaka, Y., Yamamoto, T., Morikawa, S., Yamamoto, N., Kubokawa, I., Mori, T., Yanai, T., Hayakawa, A., Takeshima, Y., Iijima, K., Matsuo, M., Nishio, H., Nishimura, N., 2012. Rab15 alternative splicing is altered in spheres of neuroblastoma cells. Oncol. Rep. 27, 2045–2049. Phillips, R.G., LeDoux, J.E., 1992. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285. Potokar, M., Lacovich, V., Chowdhury, H.H., Kreft, M., Zorec, R., 2012. Rab4 and Rab5 GTPase are required for directional mobility of endocytic vesicles in astrocytes. Glia 60, 594–604. Quadrato, G., Di Giovanni, S., 2012. Gatekeeper between quiescence and differentiation: p53 in axonal outgrowth and neurogenesis. Int. Rev. Neurobiol. 105, 71–89. Ragozzino, M.E., Unick, K.E., Gold, P.E., 1996. Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose. Proc. Natl. Acad. Sci. U.S.A. 93, 4693–4698. Roohi, J., Tegay, D.H., Pomeroy, J.C., Burkett, S., Stone, G., Stanyon, R., Hatchwell, E., 2008. A de novo apparently balanced translocation [46,XY,t(2;9)(p13;p24)] interrupting RAB11FIP5 identifies a potential candidate gene for autism spectrum disorder. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 147B, 411–417. Ropers, H.H., 2008. Genetics of intellectual disability. Curr. Opin. Genet. Dev. 18, 241–250. Sanderson, D.J., Good, M.A., Seeburg, P.H., Sprengel, R., Rawlins, J.N., Bannerman, D.M., 2008. The role of the GluR-A (GluR1) AMPA receptor subunit in learning and memory. Prog. Brain Res. 169, 159–178. Sasidharan, N., Sumakovic, M., Hannemann, M., Hegermann, J., Liewald, J.F., Olendrowitz, C., Koenig, S., Grant, B.D., Rizzoli, S.O., Gottschalk, A., Eimer, S., 2012. RAB-5 and RAB-10 cooperate to regulate neuropeptide release in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 109, 18944–18949. Schluter, O.M., Khvotchev, M., Jahn, R., Sudhof, T.C., 2002. Localization versus function of Rab3 proteins. Evidence for a common regulatory role in controlling fusion. J. Biol. Chem. 277, 40919–40929. Schluter, O.M., Schmitz, F., Jahn, R., Rosenmund, C., Sudhof, T.C., 2004. A complete genetic analysis of neuronal Rab3 function. J. Neurosci. 24, 6629–6637. Schluter, O.M., Schnell, E., Verhage, M., Tzonopoulos, T., Nicoll, R.A., Janz, R., Malenka, R.C., Geppert, M., Sudhof, T.C., 1999. Rabphilin knock-out mice reveal that rabphilin is not required for rab3 function in regulating neurotransmitter release. J. Neurosci. 19, 5834–5846. Schoch, S., Castillo, P.E., Jo, T., Mukherjee, K., Geppert, M., Wang, Y., Schmitz, F., Malenka, R.C., Sudhof, T.C., 2002. RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature 415, 321–326. Seaman, M.N., Harbour, M.E., Tattersall, D., Read, E., Bright, N., 2009. Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. J. Cell Sci. 122, 2371–2382. Shirane, M., Nakayama, K.I., 2006. Protrudin induces neurite formation by directional membrane trafficking. Science 314, 818–821. Shupliakov, O., Brodin, L., 2010. Recent insights into the building and cycling of synaptic vesicles. Exp. Cell Res. 316, 1344–1350. Stenmark, H., 2009. Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10, 513–525.

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Strick, D.J., Elferink, L.A., 2005. Rab15 effector protein: a novel protein for receptor recycling from the endocytic recycling compartment. Mol. Biol. Cell 16, 5699–5709. Teber, I., Nagano, F., Kremerskothen, J., Bilbilis, K., Goud, B., Barnekow, A., 2005. Rab6 interacts with the mint3 adaptor protein. Biol. Chem. 386, 671–677. Tisdale, E.J., Artalejo, C.R., 2006. Src-dependent aprotein kinase C iota/lambda (aPKCiota/lambda) tyrosine phosphorylation is required for aPKCiota/lambda association with Rab2 and glyceraldehyde-3-phosphate dehydrogenase on preGolgi intermediates. J. Biol. Chem. 281, 8436–8442. Torisu, H., Iwaki, A., Takeshita, K., Hiwatashi, A., Sanefuji, M., Fukumaki, Y., Hara, T., 2012. Clinical and genetic characterization of a 2-year-old boy with complete PLP1 deletion. Brain Dev. 34, 852–856. Touchot, N., Chardin, P., Tavitian, A., 1987. Four additional members of the ras gene superfamily isolated by an oligonucleotide strategy: molecular cloning of YPTrelated cDNAs from a rat brain library. Proc. Natl. Acad. Sci. U.S.A. 84, 8210–8214. Tower-Gilchrist, C., Lee, E., Sztul, E., 2011. Endosomal trafficking of the G proteincoupled receptor somatostatin receptor 3. Biochem. Biophys. Res. Commun. 413, 555–560. Tremml, P., Lipp, H.P., Muller, U., Ricceri, L., Wolfer, D.P., 1998. Neurobehavioral development, adult openfield exploration and swimming navigation learning in mice with a modified beta-amyloid precursor protein gene. Behav. Brain Res. 95, 65–76. Tsetsenis, T., Younts, T.J., Chiu, C.Q., Kaeser, P.S., Castillo, P.E., Sudhof, T.C., 2011. Rab3B protein is required for long-term depression of hippocampal inhibitory

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synapses and for normal reversal learning. Proc. Natl. Acad. Sci. U.S.A. 108, 14300–14305. Turner, L.A., Hale, C.A., Borkowski, J.G., 1996. Influence of intelligence on memory development. Am. J. Ment. Retard. 100, 468–480. van Vlijmen, T., Vleugel, M., Evers, M., Mohammed, S., Wulf, P.S., Heck, A.J., Hoogenraad, C.C., van der Sluijs, P., 2008. A unique residue in rab3c determines the interaction with novel binding protein Zwint-1. FEBS Lett. 582, 2838–2842. Vissers, L.E., de Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., de Vries, P., van Lier, B., Arts, P., Wieskamp, N., del Rosario, M., van Bon, B.W., Hoischen, A., de Vries, B.B., Brunner, H.G., Veltman, J.A., 2010. A de novo paradigm for mental retardation. Nat. Genet. 42, 1109–1112. Yamaguchi, K., Tanaka, M., Mizoguchi, A., Hirata, Y., Ishizaki, H., Kaneko, K., Miyoshi, J., Takai, Y., 2002. A GDP/GTP exchange protein for the Rab3 small G protein family up-regulates a postdocking step of synaptic exocytosis in central synapses. Proc. Natl. Acad. Sci. U.S.A. 99, 14536–14541. Zerial, M., McBride, H., 2001. Rab proteins as membrane organizers. Nat. Rev. Mol. Cell Biol. 2, 107–117. Zhang, K., Fishel Ben Kenan, R., Osakada, Y., Xu, W., Sinit, R.S., Chen, L., Zhao, X., Chen, J.Y., Cui, B., Wu, C., 2013. Defective axonal transport of Rab7 GTPase results in dysregulated trophic signaling. J. Neurosci. 33, 7451–7462. Zhao, S., Torii, S., Yokota-Hashimoto, H., Takeuchi, T., Izumi, T., 2002. Involvement of Rab27b in the regulated secretion of pituitary hormones. Endocrinology 143, 1817–1824.

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RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions.

A RAS-related class of small monomeric G proteins, the RAB GTPases, is emerging as of key biological importance in compartment specific directional co...
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