HIPPOCAMPUS 00:00–00 (2016)

Acute Systemic MK-801 Induced Functional Uncoupling Between Hippocampal Areas CA3 and CA1 With Distant Effect in the Retrosplenial Cortex  ep Helena Buchtov a, Iveta Fajnerov a, Ales Stuchlık, and St an Kubık*

ABSTRACT: The hippocampus and retrosplenial cortex are integrated within a higher-order cognitive circuit supporting relational (spatial, contextual, episodic) forms of learning and memory. Hippocampal place cells can coordinate multiple parallel representations in the same physical environment. Novel environment exploration triggers expression of immediate-early genes (IEGs) Arc and Homer1a in spatial contextspecific ensembles of CA1 and CA3 neurons. Less is know about ensemble coding in the retrosplenial cortex (RSC), a region directly connected and functionally coupled to CA1. Hippocampal and retrosplenial damage is found in patients with schizophrenia alongside cognitive deficits affecting relational memory. Systemic administration of non-competitive NMDAR antagonists such as MK-801 is used to model psychosis in animals and humans. Acute systemic MK-801 (0.15 mg/kg) impaired cognitive control in rats and ensemble code for spatial context in CA1. Here, we use expression of immediate-early genes Arc and Homer 1a to examine ensemble coding in rat CA3 and RSC to test if the effect of MK-801 extends upstream and downstream of CA1, respectively. Different rats explored the same context twice (A/A), explored two distinct contexts (A/B) or remained in their home cage (CC). In contrast to CA1, MK-801 did not affect ensemble coding in CA3. Unlike CA3 and CA1, similarity of RSC ensembles active during exploration did not reflect change in spatial context, but MK-801 (0.15 mg/kg) increased similarity in RSC ensembles active during spontaneous behavior in the home cage. The data provide support for MK-801-induced functional uncoupling between CA3 and CA1 and suggest that ensemble coding deficit may extend downstream of CA1. This deficit may reflect hyperassociative state in the cognitive circuit underlying cognitive disorganiC 2016 Wiley Periodicals, Inc. zation in psychosis. V KEY WORDS: Arc; Homer1a; catFISH; ensemble coding; cognitive control; hypersynchrony; hyperassociation; psychosis; NMDA antagonist; schizophrenia; animal model

INTRODUCTION The hippocampus is critical for episodic, spatial, and contextual memory (Eichenbaum et al., 1999; Buzsaki and Moser, 2013), but also for coordination of spatial information into meaningful representations (Kubik and Fenton, 2005; Wesierska et al., 2005). Neurons in hippocampal areas CA3 and CA1 show location-specific firing (place cells) and form ensemble representations of different spatial contexts where individual active cells may fire in multiple environments, but the active ensemble is unique for each context (Muller and Kubie, 1987; Wilson and McNaughton, 1993; Leutgeb et al., 2004). Multiple ensemble representations of the same physical environment are formed in the hippocampus, organized into subsets of coactive cells corresponding to different reference frames, which alternate on theta time scale depending on behavioral needs (Jackson and Redish, 2007; Kelemen and Fenton, 2010, Jezek et al., 2011; Kelemen and Fenton, 2013, 2016). Exploration of an environment similar to those used for place cell recordings triggers expression of immediate-early genes (IEGs) in hippocampal and neocortical neurons (Burke et al., 2005). RNA for IEGs Arc and Homer 1a induced by exploration has

Laboratory of Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic Grant sponsor: Czech Science Foundation (GACR); Grant number: 14-03627S; Grant sponsor: EU Marie Curie Grants; Grant number: PIR06-GA/2009-256581; Grant sponsor: Czech Academy of Sciences; Grant number: RVO: 67985823. Abbreviations used: A/A, repeated exploration of the same novel environment A; A/B, exploration of two distinct novel environments A and B; CA, cornu ammonis of the hippocampus; catFISH, cellular compartment analysis of temporal activity by fluorescence in situ hybridization; CC, home cage controls; EC, entorhinal cortex; GAD, glutamic acid decarboxylase; HRP, horseradish peroxidase; IEG, immediate-early gene; MK-801, dizocilpine, (1)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten5,10-imine maleate; NMDAR, N-methyl-d-aspartate receptor; OLM cells, oriens-lacunosum moleculare interneurons; PV, parvalbumin; PVI, parvalbumin-positive interneurons; RSC, retrosplenial cortex; TSA, tyramide signal amplification. *Correspondence to: Stepan Kubık, Institute of Physiology, Videnska 1083, 14220 Prague 4, Czech Republic. E-mail: stepan. [email protected] Accepted for publication 31 October 2016. DOI 10.1002/hipo.22678 Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com). C 2016 WILEY PERIODICALS, INC. V

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been used to map neuronal activity in the hippocampus during two behavioral epochs (Arc/Homer 1a catFISH; Guzowski et al., 1999; Vazdarjanova et al., 2002; Vazdarjanova and Guzowski, 2004). Ensembles activated in two distinct environments (A/B) overlap less than ensembles activated during repeated explorations of the same environment (A/A) in CA1 and CA3. Similar ensemble size and specificity to spatial context in electrophysiological recordings and IEG imaging studies suggest that location-specific firing triggers IEG expression in spatial context-specific ensembles of CA1 and CA3 neurons (Guzowski et al., 2004; Lee et al., 2004; Leutgeb et al., 2004). The hippocampus is connected to the retrosplenial cortex (RSC) in a higher-order brain circuit for episodic and spatial memory (Aggleton et al., 1986; Aggleton and Pearce, 2001; Vann et al., 2009). RSC receives direct synaptic input from the dorsal CA1 (Wyss and Van Groen, 1992; Cenquizca and Swanson, 2007; Miyashita and Rockland, 2007) and permanent lesion (Albasser et al., 2007) or reversible inactivation (Kubik et al., 2012) of the hippocampus dramatically reduces IEG expression in RSC. Neuronal activity in RSC display spatial correlates (Chen et al., 1994; Cho and Sharp, 2001) and RSC lesions impair spatial (Vann and Aggleton, 2002, 2004) and contextual memory (Keene and Bucci, 2008a). Optogenetic silencing of CA1 ensemble activated during learning impaired memory retrieval and prevented reactivation of entorhinal, perirhinal, retrosplenial, and amygdalar ensemble activity patterns established during learning (Tanaka et al., 2014). RSC inactivation impairs spatial memory (Cooper and Mizumori, 1999; Cooper, et al., 2001) and disrupts hippocampal place cell activity (Cooper and Mizumori, 2001), suggesting that RSC acts as a gateway between the hippocampus and the rest of the brain similarly to the entorhinal cortex (EC; Van Groen and Wyss, 2003). Acute systemic administration of noncompetitive antagonists of N-methyl-D-aspartate receptor (NMDAR) such as ketamine, phencyclidine, or dizocilpine (MK-801) is used to model schizophrenia because it elicits psychosis in healthy volunteers and exacerbates symptoms in patients (Krystal et al., 1994; Lahti et al., 1995; Newcomer et al., 1999; Krystal et al., 1994, 2003; Powel and Geyer, 2007; Adell et al., 2012). Hippocampal damage and profound deficits in episodic and contextual memory are hallmark impairments in schizophrenia (Hemsley, 2005; Boyer et al., 2007; Ragland et al., 2007; Ranganath et al., 2008; Tamminga et al., 2010). Cognitive deficit precedes manifestation of clinical symptoms, is most predictive of functional outcome, and least responsive to available antipsychotic medication (Ragland et al., 2007; Insel, 2010; Reichenberg et al., 2010). Patients with schizophrenia show deficit in recognizing similar, as opposed to old or new items (Das et al., 2014). Impaired cognitive coordination has been described as a core deficit in schizophrenia (Phillips and Silverstein, 2003). In our previous study, we showed that the same dose of MK-801 (0.15 mg/kg) that impaired cognitive coordination in rats avoiding an unmarked place on a continuously rotating arena (Carousel) also compromised the ability of CA1 to form Hippocampus

separate ensemble representations of different environments (Kubik et al., 2014). In the present study, we examined if the ensemble coding deficit was also present upstream and downstream of CA1. We used Arc/Homer 1a two time-point FISH imaging to examine the effect of MK-801 (0, 0.10, and 0.15 mg/kg) on ensemble coding for spatial context in CA3 and RSC. The CA1 data has been previously reported in the context of parallel behavioral experiments (Kubik et al., 2014) and are replicated here solely to facilitate comparisons across the cognitive circuit. We show that ensemble coding in CA3 is unaffected by either dose of MK-801. Lack of ensemble coding for spatial context prevented testing this deficit in RSC. However, selective increase in ensemble similarity in RSC of cage controls (CC) after MK-801 (0.15 mg/kg) suggests that overlap between unrelated representations may be increased also downstream of CA1.

MATERIALS AND METHODS Subjects The present study used tissue samples from the same animals that provided IEG image data from CA1, which were published previously (Kubik et al., 2014). Analysis of the CA1 data was recalculated to match the analysis of CA3 and RSC and is shown here solely to provide the circuit context for the present data. The methods for behavioral induction of IEG expression by novel environment exploration and catFISH image data analysis were described previously (Vazdarjanova and Guzowski, 2004; Kubik et al., 2012, 2014). In total, 42 young (2.5 months) male Long-Evans rats from the Institute of Physiology breeding colony were maintained on a 12/12 light/ dark cycle and tested during the light phase. During the experiments they were housed individually in opaque cages with food and water available ad libitum.

Behavioral Procedures The rats were handled at least 3 days and on the experimental day they received two exploration sessions lasting 5 min and separated by a 20 min intersession interval in their home cages to maximize detection of IEG RNA triggered by the exploration (Fig. 1). The rats explored either the same environment twice (A/A) or two distinct environments (A/B). Environment A was a circular metallic platform 82 cm in diameter equipped with transparent wall and three identical objects (dark plastic cylinders 8 cm high 2 cm diameter) and environment B was a square open field of equivalent size (72 cm) equipped with three wooden blocks 3 3 6 3 6 cm3 located in a different room. Home cage controls (CC) received no exploration and spent the time undisturbed in their home cages to provide baseline IEG expression. Thirty minutes before the first exploration session, the rats received saline or 0.10 or 0.15 mg/

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FIGURE 1. Patterns of IEG expression in the hippocampalretrosplenial system. (A) Schematic of behavioral induction of Arc and Homer1a expression in the hippocampus and retrosplenial cortex (RSC) by novel environment exploration. Homer 1a signal (green) marks neurons activated during Epoch 1 because the probe targets 50 UTR of 30 end of the primary transcript (~45 kb). It only appears in the nuclei ~25 min after the inducing stimuli. Arc signal (magenta) marks neurons activated during Epoch 2. Exploration triggers IEG expression in spatial context-specific ensembles in the hippocampus, where ensemble overlap (double-labeled neurons) is high in A/A and low in A/B. In the retrosplenial cortex, the overlap is high even between ensembles active in different

environments A and B. (B, C, D) Representative Arc/Homer1a FISH images of hippocampal areas CA3, CA1, and RSC with different MK-801 treatment and behavioral exposure to the same (A/ A) or different environments (A/B). Control rats remained in their home cages (CC). Images of CA1 and RSC were acquired on an inverted laser scanning microcope (Leica SP5) using apochromatic objective HCX PL APO 20x (n.a. 0.7) imm corr and CA3 images with objective HCX PL APO 103 (n.a. 0.40). Signals from Homer1a (green) and Arc (red) riboprobes appear as bright intranuclear foci. Nuclear counterstain (DAPI) is shown in blue. [Color figure can be viewed at wileyonlinelibrary.com]

kg MK-801 in 1 ml/kg (i.p.). We used six groups of five animals with different treatment (0, 0.10, and 0.15 mg/kg MK801) and exploration (A/A, A/B) and a group of four cage controls per each treatment.

Tissue Processing and FISH Image Data Acquisition

Drugs MK-801 (dizocilpine, (1)-5-methyl-10,11-dihydro-5Hdibenzocyclohepten-5,10-imine maleate; Sigma) was diluted in sterile physiological saline at low (0.10 mg/kg) or high (0.15 mg/ml) dose.

Immediately after the second test session rats were deeply anesthetized with isoflurane and decapitated, their brains were quickly removed, flash-frozen in dry ice-cooled isopentane bath and stored in 2808C freezer for later analysis. Four millimeter segments containing the dorsal hippocampus from left hemispheres were arranged in blocks maximizing the number of within-block, between-group comparisons and embedded in optimal cutting temperature medium (OCT; Sakura). The blocks were sectioned at 20 lm in a cryostat (Leica CM 1850, Germany), mounted on Hippocampus

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gelatine-coated superfrost slides (ThermoFisher), and processed as previously described (Vazdarjanova and Guzowski, 2004; Kubik et al., 2012). Briefly, fluorescein-labeled antisense riboprobes for Homer 1a 30 UTR and digoxigenin-labeled Arc antisense riboprobes were hybridized overnight in a single hybridization step and then sequentially detected with antifluorescein conjugated with horseradish peroxidase (HRP, Jackson ImmunoResearch) and antidigoxigenin-HRP FAB fragments (Roche). Homer 1a probes were visualized with tyramide-fluorescein signal amplification system (TSA-Fluorescein) and Arc probes with TSA-Cy3 (Perkin-Elmer). Slides were incubated with nuclear counterstain (DAPI, Invitrogen, ThermoFisher), coverslipped with antifade media (Vectashield, Vector labs), and sealed with nail polish. Confocal stacks from RSC were acquired on an inverted Leica SP5 laser scanning microscope with apochromatic objective HCX PL APO 203 (n.a. 0.7) imm corr Lbd. BL. Images of CA3 were obtained using objective HCX PL APO 103 (n.a. 0.40) CS. Blue signal (DAPI) was imaged using 405 nm excitation and 415–490 bandpass, green signal (TSA-Fluorescein) with 488 nm excitation and 510–550 bandpass and orange signal (TSA-Cy3) with 561 nm laser and 610–680 bandpass. The laser power, gain, and offset were always set for the whole slide. The settings were optimized to obtain bright intranuclear foci of ongoing IEG transcription. We analyzed on average 374 6 5.3 CA3 cells in two images and 1585 6 29 RSC cells in eight images per animal.

Data Analysis The image data were analyzed by a technician blind to the identity of the samples using a custom macro for ImageJ as described before (Kubik et al., 2012). Expression of Homer 1a1 and Arc1 was used to map neuronal populations active during the first and second test session, respectively. The effect of psychotomimetic MK-801 on IEG expression and on ensemble similarity was analyzed separately for each region. First, we examined the effect of novel environment exploration on IEG expression. The different context groups (A/A and A/B) were merged (Exploration) and as compared to the home cage control (CC) animals using a three-way ANOVA with main factors of TREATMENT (saline, 0.10 and 0.15 mg/kg MK-801) and BEHAVIOR (Exploration vs. CC) and repeated measures on the proportions of Homer1a1 and Arc1 cells, corresponding to the populations activated during test sessions 1 and 2, respectively. The effect of MK-801 on the exploration-induced IEG expression was analyzed using three-way ANOVA with main factors of TREATMENT and CONTEXT and repeated measures on the proportions of Homer1a1 and Arc1 cells. Second, we compared the effect of MK-801 on similarity of ensembles activated by exploration of the same (A/A) or different (A/B) environments using a two-way ANOVA with main factors of TREATMENT and CONTEXT (A/A vs. A/B) on similarity scores. The similarity scores (Vazdarjanova and Guzowski, 2004; Burke et al., 2005; Nomura et al., 2012; Kubik et al., 2014) were calculated as difference between the observed and expected overlap divided by difference between smaller of the two populations and the expected overlap: ss 5 diff(E1E2)/(least epoch - p(E1E2)), where Hippocampus

E1 and E2 are proportions of Homer 1a1 and Arc1 neurons, respectively, out of all observed neurons, p(E1E2) 5 E1*E2 is expected random overlap based on the product of these proportions, least epoch is smaller of E1 and E2, and diff(E1E2) 5 (Arc&Homer 1a)1 - p(E1E2) is a difference between the observed proportion of double-labeled neurons and the random overlap. Third, we tested specific effects of MK-801 on overall IEG expression and ensemble similarity in CC animals using a two-way ANOVA with a main factor of TREATMENT and repeated measures on proportions of Homer1a1 and Arc1 cells, and one-way ANOVA on similarity scores, respectively.

RESULTS MK-801 Reduces Exploration-Induced IEG Expression Exploration of novel environments (A/A or A/B) massively induced IEG expression as compared to home cage controls (CC) and MK-801 reduced this expression (Fig. 1B–D). A three-way ANOVA with repeated measures on the proportions of Arc1 and Homer1a1 neurons found highly significant effects of BEHAVIOR (Exploration vs. CC) in CA3 (F1,36 5 91.5, P < 1026), CA1 (F1,36 5 25.2, P < 1024), and RSC (F1,36 5 27.2, P < 1025). Given this overwhelming effect of behavioral exploration, all further analyses were performed separately in the exploration and CC animals. A separate analysis of exploration-induced IEG expression (Fig. 2) confirmed significant effects of TREATMENT in CA3 (F2,24 5 11.2, P < 0.0005), CA1 (F2,24 5 9.48, P < 0.001), and RSC (F2,24 5 6.77, P < 0.005). Post hoc tests revealed a dosedependent decrease in CA3 (all P < 0.05) and doseindependent decrease in CA1 and RSC (saline vs. MK-801 all P < 0.01; low vs. high P > 0.3). Baseline IEG expression in the CC was reduced by MK-801 (Fig. 3) in CA1 (F2,9 5 21.3, P < 1024), but not in CA3 (F2,9 5 0.43, P > 0.6) or RSC (F2,9 5 1.23, P > 0.3). Post hoc test showed that the reduction in CA1 was dose-independent (low vs. high P > 0.7).

Hippocampal but Not Retrosplenial Ensembles Code for Spatial Context Ensemble similarity was markedly higher in rats exploring the same context (A/A) compared to different contexts (A/B) in CA3 and CA1 (Fig. 4A,B), but not in RSC (Fig. 4C). A two-way ANOVA on ensemble similarity scores found highly significant effects of CONTEXT (A/A vs. A/B) in CA3 (F1,24 5 43.3, P < 1025) and CA1 (F1,24 5 34.1, P < 1025), but not in RSC (F1,24 5 0.62, P > 0.4).

MK-801 Did Not Affect Ensemble Coding in CA3 MK-801 did not affect ensemble code for spatial context in CA3 (Fig. 4A). The two-way ANOVA on ensemble similarity

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FIGURE 2. Effect of MK-801 on IEG expression induced by novel environment exploration. Different groups of animals were exposed to the same (A/A) or to different (A/B) environments. (A) MK-801 dose-dependently reduced IEG expression in CA3 (F2,24 5 11.2, P < 0.0005). *P < 0.05 (0.10 vs. vehicle); #P < 0.0005

(0.15 vs. vehicle), P < 0.05 (0.15 vs. 0.10). (B) Adapted from Kubik et al. (2014). MK-801 reduced IEG expression in CA1 in a dose-independent manner (F2,24 5 9.48, P < 0.001). $P < 0.005. (C) MK-801 reduced IEG expression in RSC in a doseindependent manner (F2,24 5 6.77, P < 0.005). ‡P < 0.01.

scores found neither effect of TREATMENT (F2,24 5 1.91, P > 0.15) nor TREATMENT x CONTEXT interaction (F2,24 5 0.83, P > 0.4) in CA3 of the exploring animals. No effect of the MK-801 TREATMENT on CA3 ensemble similarity was found in cage control animals either (F2,9 5 0.38, P > 0.6).

and the low dose (P < 0.0005), but not after the high dose of MK-801 (P > 0.5), when ensemble similarity in A/B was increased compared to saline and the low dose (P < 0.05) to a level equivalent to the A/A condition with all treatments (P > 0.12). No significant effect of TREATMENT on CA1 ensemble similarity was found in cage controls (F2,9 5 2.61, P 5 0.127).

MK-801 Increased Similarity Between CA1 Ensemble Representations of Different Environments A/B The CA1 data were reported previously (Kubik et al., 2014). The high (0.15 mg/kg), but not the low (0.10 mg/kg) dose of MK-801 increased similarity between CA1 ensembles activated in different spatial contexts (A/B) to the level of the same context (A/A; Fig. 4B). The two-way ANOVA on ensemble similarity scores found a significant TREATMENT 3 CONTEXT interaction (F2,24 5 5.96, P < 0.01) with no main effect of TREATMENT (F2,24 5 0.59, P > 0.5). Post hoc tests revealed that ensemble similarity was much higher in the same context (A/A) than in different contexts (A/B) after saline (P < 0.005)

MK-801 Increased Ensemble Similarity in RSC of Cage Controls MK-801 did not affect similarity between RSC ensembles activated by exploration. The two-way ANOVA on ensemble similarity scores found no significant effect of TREATMENT (F2,24 5 2.79, P 5 0.081) or TREATMENT 3 CONTEXT interaction (F2,24 5 0.27, P > 0.7) in the exploring animals. However, the high dose of MK-801 increased ensemble similarity in the CC (F2,9 5 18.6, P < 0.001) relative to saline (P < 0.005) and the low dose of MK-801 (P < 0.001; Fig. 4C). Hippocampus

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FIGURE 3. Effect of MK-801 on baseline IEG expression in home cage controls (CC). (A) MK-801 did not affect baseline IEG expression in CA3 (F2,9 5 0.43, P > 0.6). (B) Adapted from Kubik et al. (2014). MK-801 reduced baseline IEG expression in CA1 in a doseindependent manner (F2,9 5 21.3, P < 0.0005). *P < 0.001. (C) MK-801 did not affect baseline IEG expression in RSC (F2,9 5 1.23, P > 0.3).

DISCUSSION In agreement with previous studies (Guzowski et al., 1999; Vazdarjanova and Guzowski, 2004; Kubik et al., 2014), exploration reliably induced Arc and Homer1a expression compared to the CC (Fig. 5). This behaviorally induced expression was markedly reduced by MK-801 in all regions, presumably due to MK-801 interfering with NMDAR-dependent induction of IEG expression (Czerniawski et al., 2011). This reduction was flat in CA1 and RSC, but a dose-dependent effect was observed in CA3. In contrast, baseline IEG expression in CC was only affected in CA1. Together with the CA1 data, the lack of effect of MK-801 on ensemble coding in CA3 indicates that the two regions have been functionally uncoupled after 0.15 mg/kg MK-801. This finding dovetails with the notion that NMDAR antagonists may suppress information flow from CA3 to CA1 along Schaffer collaterals in the favor of the direct temporoammonic pathway from the EC (Caixeta et al., 2013; Cabral et al., 2014). NMDAR activity substantially contribute to basal excitatory synaptic transmission in interneurons, which show greater sensitivity to NMDA antagonist (Jones and B€ uhl, Hippocampus

1993; Grunze et al., 1996, 2000). OLM cells are inhibitory interneurons located in stratum oriens and projecting to stratum lacunosum-moleculare, which gate information flow to CA1 by reducing the influence of the EC input and facilitating neurotransmission from CA3 (Le~ao et al., 2012). They also express different types of NMDAR than pyramidal neurons (Hajos et al., 2002). Interestingly, ensemble distinctiveness in CA1 was enhanced after transient partial inactivation of medial EC (Rueckemann et al., 2015), when additional layers of dentate gyrus and CA3 could have shifted the balance in CA1 inputs in favor of the trisynaptic pathway. Whereas ensembles of CA3 and CA1 neurons expressed IEGs Arc and Homer1a in spatial context-specific manner, RSC ensembles did not display reliable specificity to spatial context. Ensemble similarity in different environments (A/B) was equivalent to the same environments (A/A; Figs. 1, 4C, and 5) and could not be increased by MK-801. The spatial contextindependence may be due to the RSC ensembles coding for some other dimension of behavioral experience such as reward value or behavioral choices. Direct optogenetic reactivation of RSC ensemble active during fear conditioning produced context-specific behavior and downstream cellular activity in

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FIGURE 4. Effect of MK-801 on ensemble coding. (A) Ensemble similarity in CA3 was substantially higher in A/A than in A/B condition (F1,24 5 43.3, P < 1025), irrespective of MK-801 (F2,24 5 1.91, P > 0.15). *P < 0.01; #P < 0.005. No effect of MK801 was observed in the CC. (B) Adapted from Kubik et al. (2014). In CA1, the ensemble similarity in A/A was higher than in A/B after saline and the low dose (0.10 mg/kg) of MK-801 (F1,24 5 34.1, P < 1025), but the high dose (0.15 mg/kg) increased

ensemble similarity in A/B to the A/A level (F2,24 5 5.96, P < 0.01). *P < 0.01; $P < 0.001. No effect of MK-801 was observed in the CC. (C) Ensemble similarity in RSC was not affected by change of spatial context (F1,24 5 0.62, P > 0.4). However, the high dose of MK-801 increased ensemble similarity in CC compared to vehicle and the low dose (F2,9 5 18.6, P < 0.001). ‡P < 0.005.

Amygdala and EC despite hippocampal inactivation, showing that ensemble activity in RSC can control behavioral responses and downstream areas of the cognitive circuit (Cowansage et al., 2014). Testing if MK-801 increases overlap between behaviorally activated RSC ensembles will require a task which would provide better contrast between the same and different conditions. Such task may involve changes in behavioral contingencies (direction on a linear track, reinforcement, target location). It is also possible that ensemble specificity in RSC only develops as a result of specific learning. RSC neurons display experiencedependent activity (Czajkowski et al., 2014) and develop reward location–specific responses (Smith et al., 2012). The increase in ensemble similarity induced by MK-801 in RSC in the absence of overt exploratory behavior in the home cage (CC) suggests that overlap between unrelated representations may be increased also downstream of CA1. However, the proportions of active cells in RSC of CC animals were very low (0.5–2%), driving the theoretical parameter of random

overlap obtained as a product of two such proportions close to zero. To further verify the result, we used an alternative measure of population similarity avoiding the random overlap parameter, the Sørensen-Dice index (Dice, 1945), SDi 5 2*(Arc & Homer 1a)1/(E1 1 E2), where (Arc & Homer 1a) 1 is the proportion of double-positive cells (i.e., the observed overlap) and E1 and E2 are the proportions of cells active in epochs 1 and 2, respectively. This parameter confirmed highly significant (P < 1025) increase in RSC ensemble similarity in CC selectively after 0.15 mg/kg MK-801. In fact, all double-positive RSC cells in the CC (13 in total) were observed after the high dose of MK-801. The low activity in CC may reflect rare salient events or external stimuli occurring randomly during spontaneous behavior in the home cage. Different events occur during the test epochs, resulting in low ensemble similarity. Ensemble code for spatial context is absent in CA1 of mice after contextual fear conditioning (Nomura et al., 2012) and it may be absent in the home cage as well. Hippocampus

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FIGURE 5. Schematic of MK-801-induced alterations of ensemble coding in CA3 and CA1 of the hippocampus and in the retrosplenial cortex. Animals exposed to the same (A/A), different (A/B), or no (CC) environments are organized in columns. The ovals represent ensembles active in epochs 1 and 2. The black area represents ensemble overlap. The size of the ovals represents the ensemble size. Note the dose-dependent ensemble reduction and lack of effect of MK-801 on ensemble similarity in CA3, the dosedependent increase in ensemble similarity in different environments (A/B) in CA1, and the lack of ensemble coding for spatial context and dose-dependent increase in CC ensemble similarity in RSC. MK-801-induced increase in CA1 ensemble similarity specific to the A/B condition was reported previously (Kubik et al., 2014).

OLM cells are likely not the only class of interneurons responsible for the effect of NMDAR antagonists on cognitive coordination and ensemble coding in the cognitive circuit. Reduced expression of glutamic acid decarboxylase (GAD67), parvalbumin (PV), and somatostatin in several brain regions including the hippocampus is consistently found in schizophrenia (Zhang and Reynolds, 2002; Behrens and Sejnowski, 2009; Gonzalez-Burgos et al., 2010; Konradi et al., 2011), after NMDAR antagonist treatment (Keilhoff et al., 2004; Behrens et al., 2007; Romon et al., 2011), and in neurodevelopmental models (Powell et al., 2012). Fast-spiking PV1 interneurons (PVI) synchronize large numbers of pyramidal neurons and critically contribute to gamma oscillations, theta modulation and theta-gamma coupling (Bartos et al., 2007; Sohal et al., 2009; Wulff et al., 2009). NMDAR hypofunction on PVI can disrupt synchronization of neural circuit activity, cause excessive spread of excitatory synaptic association, and impair coordination of higher-order cognitive processes (Lewis et al., 2005; Lisman et al., 2008; Nakazawa et al., 2012). It can also reduce hippocampal theta and augment gamma oscillations and impair cognitive coordination as observed in schizophrenia (Neymotin et al., 2011; Tort et al., 2007). Mice with selective genetic ablation of NMDAR in PVI display behavioral deficits and alterations of neural oscillations similar to schizophrenia (Belforte et al., 2010; Korotkova et al., 2010). MK-801 reduces firing rates of fast-spiking interneurons, increases firing in pyramidal neurons (Homayoun and Moghaddam, 2007), and cause hyperactivity in excitatory circuits in the hippocampus and retrosplenial cortex (Miyamoto et al., 2000; Li et al., 2002; Heckers and Konradi, 2015). Such disinhibition may Hippocampus

give rise to hypersynchrony and hyperassociation manifested as reduced distinctiveness of ensemble representations. Hypersynchrony was described in hippocampal recordings after contralateral hippocampal inactivation or systemic phencyclidine (Fenton, 2009). It refers to a specific increase in coactivity between initially noncoactive neurons (such as between neurons from different ensembles representing different environments), but not between neurons that were already coactive (such as neurons from the same ensemble). Hypersynchrony could increase binding and similarity between ensemble representations of unrelated events. Increased reactivation of the same cells may contribute to neuronal damage observed in RSC after systemic NMDAR antagonist treatment (Olney et al., 1989) and even after a single dose of MK-801 (Horvath et al., 1997). Altered RSC activity and connectivity have also been observed in patients with schizophrenia (Tendolkar et al., 2004; Bluhm et al., 2009; Lee et al., 2015) and reduced RSC volume is associated with poor patient outcome (Mitelman et al., 2005). In animal models, RSC lesions impair response conflict resolution based on contextual cues in a rodent analogy of the Stroop Test of cognitive control used to assess cognitive deficit in schizophrenia (Nelson et al., 2014). RSC lesions also impaired discrimination of simultaneously presented stimuli (Keene and Bucci, 2008b) and avoidance of a stationary place on a continuously rotating arena when spatial reference frames were dissociated (Wesierska et al., 2009), in support of the view that RSC participates in coordination of spatial cognition and behavior in multiple reference frames (Iaria et al., 2007; Vann et al., 2009). In summary, we have shown that, unlike in CA1, MK-801 (0.15 mg/kg) did not affect ensemble coding in CA3, suggesting it caused functional uncoupling between the two areas. MK-801 (0.15 mg/kg) increased RSC ensemble similarity during spontaneous activity in the home cage, suggesting that MK-801-induced ensemble coding deficit may affect cognitive representations beyond CA1. Ensemble codes must avoid representing multiple items with the same cells to prevent memory interference and information loss (Hebb, 1949; von der Malsburg, 1994, McNaughton and Wickens, 2003). Merging representations of distinct contexts or events could lead to the excessive associations, episodic and contextual memory deficits, and cognitive disorganization in schizophrenia (Miller, 1989; Phillips and Silverstein, 2003; Manschreck et al., 2012; Fenton, 2015). The deficit in ensemble coding may be an endophenotype of cognitive disorganization in psychosis and it could potentially be used to test the efficacy of novel pro-cognitive antipsychotics.

Acknowledgments The authors wish to thank Dr. John F. Guzowski of UCI Irvine for generously providing the DNA constructs for riboprobe synthesis, Aaron J. Schiffman for developing the ImageJ macro for the analysis, Jana Machkova for tissue processing, Barbara Stuchlıkova for image processing and analysis, and Dr.

MK-801 CAUSES HIPPOCAMPAL UNCOUPLING Edo Kelemen for valuable comments on earlier versions of the manuscript.

REFERENCES Adell A, Jimenez-Sanchez L, Lopez-Gil X, Romon T. 2012. Is the acute NMDA receptor hypofunction a valid model of schizophrenia? Schizophr Bull 38:9–14. Aggleton JP, Hunt PR, Rawlins JNP. 1986. The effects of hippocampal lesions upon spatial and non-spatial tests of working memory. Behav Brain Res 19:133–146. Aggleton JP, Pearce MW. 2001. Neural systems underlying episodic memory: Insights from animal research. Phil Trans R Soc London: Biol 356:1467–1482. Albasser MM, Poirier GL, Warburton EC, Aggleton JP. 2007. Hippocampal lesions halve immediate-early gene protein counts in retrosplenial cortex: Distal dysfunctions in a spatial memory system. Eur J Neurosci 26:1254–1266. Bartos M, Vida I, Jonas P. 2007. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci 8:45–56. Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan LL. 2007. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318:1645–1647. Behrens MM, Sejnowski TJ. 2009. Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex? Neuropharmacology 57:193–200. Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K. 2010. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13:76–83. Bluhm RL, Miller J, Lanius RA, Osuch EA, Boksman K, Neufeld RW, Theberge J, Schaefer B, Williamson PC. 2009. Retrosplenial cortex connectivity in schizophrenia. Psychiatry Res 174:17–23. Boyer P, Phillips JL, Rousseau FL, Ilitvitsky S. 2007. Hippocampal abnormalities and memory deficits: New evidence of a strong pathophysiological link in schizophrenia. Brain Res Rev 54:92–112. Burke SN, Chawla MK, Penner MR, Crowell BE, Worley PF, Barnes CA, McNaughton BL. 2005. Differential encoding of behavior and spatial context in deep and superficial layers of the neocortex. Neuron 45:667–674. Buzsaki G, Moser EI. 2013. Memory, navigation and theta rhythm in the hippocampal-entorhinal system. Nat Neurosci 16:130–138. Cabral HO, Vinck M, Fouquet C, Pennartz CM, Rondi-Reig L, Battaglia FP. 2014. Oscillatory dynamics and place field maps reflect hippocampal ensemble processing of sequence and place memory under NMDA receptor control. Neuron 81:402–415. Caixeta FV, Cornelio AM, Scheffer-Teixeira R, Ribeiro S, Tort ABL. 2013. Ketamine alters oscillatory coupling in the hippocampus. Sci Rep 3:2348. Cenquizca LA, Swanson LW. 2007. Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex. Brain Res Rev 56:1–26. Chen LL, Lin LH, Green EJ, Barnes CA, McNaughton BL. 1994. Head-direction cells in the rat posterior cortex. I. Anatomical distribution and behavioral modulation. Exp Brain Res 101:8–23. Cho J, Sharp PE. 2001. Head direction, place, and movement correlates for cells in the rat retrosplenial cortex. Behav Neurosci 115: 3–25. Cooper BG, Mizumori SYJ. 1999. Retrosplenial cortex inactivation selectively impairs navigation in the dark. NeuroReport 10:625– 630.

9

Cooper BG, Mizumori SYJ. 2001. Temporary inactivation of the retrosplenial cortex causes transient reorganization of spatial coding in the hippocampus. J Neurosci 21:3986–4001. Cooper BG, Manka TF, Mizumori SJY. 2001. Finding your way in the dark: The retrosplenial cortex contributes to spatial memory and navigation without visual cues. Behav Neurosci 115:1012– 1028. Cowansage KK, Shuman T, Dillingham BC, Chang A, Golshani P, Mayford M. 2014. Direct reactivation of a coherent neocortical memory of context. Neuron 84:432–441. Czajkowski R, Jayaprakash B, Wiltgen B, Rogerson T, GuzmanKarlsson MC, Barth AL, Trachtenberg JT, Silva AJ. 2014. Encoding and storage of spatial information in the retrosplenial cortex. Proc Natl Acad Sci U S A 111:8661–8666. Czerniawski J, Ree F, Chia C, Ramamoorthi K, Kumata Y, Otto TA. 2011. The importance of having Arc: Expression of the immediate-early gene Arc is required for hippocampus-dependent fear conditioning and blocked by NMDA receptor antagonism. J Neurosci 31:11200–11207. Das T, Ivleva EI, Wagner AD, Stark CE, Tamminga CA. 2014. Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction. Schizophr Res 159:193–7. Dice LR. 1945. Measures of the amount of ecologic association between species. Ecology 26:297–302. Eichenbaum H, Dudchenko P, Wood E, Shapiro M, Tanila H. 1999. The hippocampus, memory, and place cells: Is it spatial memory or a memory space? Neuron 23:209–226. Fenton AA. 2009. Neural coordination and psychotic disorganization. In Holscher C, Munk MH, editor. Information Processing by Neuronal Populations. London: Cambridge University Press. pp 387–408. Fenton AA. 2015. Excitation-inhibition discoordination in rodent models of mental disorders. Biol Psychiatry 77:1079–1088. Gonzalez-Burgos G, Hashimoto T, Lewis DA. 2010. Curr Psychiatry Rep 12:335–344. Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, Greene RW. 1996. NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 16:2034–2043. Grunze H, Bender A, Wendhof S, Sch€afer M, Rujescu D. 2000. Neurotoxicity of NMDA antagonists: A glutamatergic theory of schizophrenia based on selective impairment of local inhibitory feedback circuits. Dialogues Clin Neurosci 2:287–298. Guzowski JF, McNaughton BL, Barnes CA, Worley PF. 1999. Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat Neurosci 2:1120–1124. Guzowski JF, Knierim JJ, Moser EI. 2004. Ensemble dynamics of hippocampal regions CA1 and CA3. Neuron 44:581–584. Hajos N, Freund TF, Mody I. 2002. Comparison of single NMDA receptor channels recorded on hippocampal principal cells and oriens/alveus interneurons projecting to stratum lacunosummoleculare (O-LM cells). Acta Biol Hung 53:465–472. Hebb D. 1949. The Organization of Behavior, a Neuropsychological Theory. New York: Wiley. Heckers S, Konradi C. 2015. GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. Schizophr Res 167:4–11. Hemsley DR. 2005. The schizophrenic experience: Taken out of context? Schiz Bull 31:43–53. Homayoun H, Moghaddam B. 2007. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496–11500. Horvath ZC, Czopf J, Buzsaki G. 1997. MK-801-induced neuronal damage in rats. Brain Res 753:181–195. Iaria G, Chen J-K, Guariglia C, Ptito A, Petrides M. 2007. Retrosplenial and hippocampal brain regions in human navigation: Complementary functional contributions to the formation and use of cognitive maps. Eur J Neurosci 25:890–899. Insel TR. 2010. Rethinking schizophrenia. Nature 468:187–193. Hippocampus

10

 ET AL. BUCHTOVA

Jackson J, Redish AD. 2007. Network dynamics of hippocampal cellassemblies resemble multiple spatial maps within single tasks. Hippocampus 17:1209–1229. Jezek K, Henriksen EJ, Treves A, Moser EI, Moser M-B. 2011. Thetapaced flickering between place-cell maps in the hippocampus. Nature 478:246–249. Jones RS, B€ uhl EH. 1993. Basket-like interneurones in layer II of the entorhinal cortex exhibit a powerful NMDA-mediated synaptic excitation. Neurosci Lett 149:35–39. Keene CS, Bucci DJ. 2008a. Contributions of the retrosplenial and posterior parietal cortices to cue-specific and contextual fear conditioning. Behav Neurosci 122:89–97. Keene CS, Bucci DJ. 2008b. Involvement of the retrosplenial cortex in processing multiple conditioned stimuli. Behav Neurosci 122: 651–658. Kelemen E, Fenton AA. 2010. Dynamic grouping of hippocampal neural activity during cognitive control of two spatial frames. PLoS Biol 8:e1000403. Kelemen E, Fenton AA. 2013. Key features of human episodic recollection in the cross-episode retrieval of rat hippocampus representations of space. PLoS Biol 11:e1001607. Kelemen E, Fenton AA. 2016. Coordinating different representations in the hippocampus. Neurobiol Learn Mem 129:50–59. Keilhoff G, Becker A, Grecksch G, Wolf G, Bernstein HG. 2004. Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia. Neuroscience 126:591–598. Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, Berretta S, Heckers S. 2011. Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res 131: 165–173. Korotkova T, Fuchs EC, Ponomarenko A, von Engelhardt J, Monyer H. 2010. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68:557–569. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. 1994. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214. Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. 2003. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berlin) 169:215–233. Kubik S, Fenton AA. 2005. Behavioral evidence that segregation and representation are dissociable hippocampal functions. J Neurosci 25:9205–9212. Kubik S, Miyashita T, Kubik-Zahorodna A, Guzowski JF. 2012. Loss of activity-dependent Arc gene expression in the retrosplenial cortex after hippocampal inactivation: interaction in a higher-order memory circuit. Neurobiol Learn Mem 97:124–131. Kubik S, Buchtova H, Vales K, Stuchlik A. 2014. MK-801 impairs cognitive coordination on a rotating arena (Carousel) and contextual specificity of hippocampal immediate-early gene expression in a rat model of psychosis. Front Behav Neurosci 8:75. Lahti AC, Koffel B, LaPorte D, Tamminga CA. 1995. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19. Le~ao RN, Mikulovic S, Le~ao KE, Munguba H, Gezelius H, Enjin A, Patra K, Eriksson A, Loew LM, Tort AB, Kullander K. 2012. OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons. Nat Neurosci 15:1524– 1530. Lee I, Yoganarasimha D, Rao G, Knierim JJ. 2004. Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3. Nature 430:456–459. Hippocampus

Lee JS, Chun JW, Lee SH, Kim E, Lee SK, Kim JJ. 2015. Altered neural basis of the reality processing and its relation to cognitive insight in schizophrenia. PLoS One 10:e0120478. Leutgeb S, Leutgeb JK, Treves A, Moser M-B, Moser EI. 2004. Distinct ensemble codes in hippocampal areas CA3 and CA1. Science 305:1295–1298. Lewis DA, Hashimoto T, Volk DW. 2005. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324. Li Q, Clark S, Lewis DV, Wilson WA. 2002. NMDA receptor antagonists disinhibit rat posterior cingulate and retrosplenial cortices: A potential mechanism of neurotoxicity. J Neurosci 22:3070–3080. Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S, Grace AA. 2008. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 31:234–242. von der Malsburg C. 1994. The correlation theory of brain function. (MPI Biophysical Chemistry, internal report 81-82, 1981). In: Domany E, van Hemmen JL, Schulten K, editors. Models of Neural Networks II. Berlin: Springer. Manschreck TC, Merrill AM, Jabbar G, Chun J, Delisi LE. 2012. Frequency of normative word associations in the speech of individuals at familial high-risk for schizophrenia. Schizophr Res 140:99– 103. McNaughton N, Wickens J. 2003. Hebb, pandemonium and catastrophic hypermnesia: The hippocampus as a suppresor of inappropriate associations. Cortex 39:1139–1163. Miller R. 1989. Hyperactivity of associations in psychosis. Aust NZJ Psychiatry 23:241–248. Mitelman SA, Shihabuddin L, Brickman AM, Hazlett EA, Buchsbaum MS. 2005. Volume of the cingulate and outcome in schizophrenia. Schizophr Res 72:91–108. Miyamoto S, Leipzig JN, Lieberman JA, Duncan GE. 2000. Effects of ketamine, MK-801, and amphetamine on regional brain 2deoxyglucose uptake in freely moving mice. Neuropsychopharmacology 22:400–412. Miyashita T, Rockland KS. 2007. GABAergic projections from the hippocampus to the retrosplenial cortex in the rat. Eur J Neurosci 26:119321204. Muller RU, Kubie JL. 1987. The effects of changes in the environment on the spatial firing of hippocampal complex-spike cells. J Neurosci 7:1951–1968. Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, Belforte JE. 2012. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology 62:1574–1583. Nelson AJ, Hindley EL, Haddon JE, Vann SD, Aggleton JP. 2014. A novel role for the rat retrosplenial cortex in cognitive control. Learn Mem 21:90–97. Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW. 1999. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106–118. Neymotin SA, Lazarewicz MT, Sherif M, Contreras D, Finkel LH, Lytton WW. 2011. Ketamine disrupts u modulation of g in a computer model of hippocampus. J Neurosci 31:11733–11743. Nomura H, Nonaka A, Matsuki N. 2012. Population activity in the dorsal hippocampal CA1 encoding the surrounding environment is absent during contextual fear memory expression. Neuroscience 220:19–25. Olney JW, Labruyere J, Price MT. 1989. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244:1360–1362. Phillips WA, Silverstein SM. 2003. Convergence of biological and psychological perspectives on cognitive coordination in schizophrenia. Behav Brain Sci 26:65–82. Powel SB, Geyer MA. 2007. Overview of animal models of schizophrenia. Curr Protoc Neurosci 39:24.

MK-801 CAUSES HIPPOCAMPAL UNCOUPLING Powell SB, Sejnowski TJ, Behrens MM. 2012. Behavioral and neurochemical consequences of cortical oxidative stress on parvalbumininterneuron maturation in rodent models of schizophrenia. Neuropharmacol 62:1322–1331. Ragland JD, Yoon J, Minzenberg MJ, Carter CS. 2007. Neuroimaging of cognitive disability in schizophrenia: Search for a pathophysiological mechanism. Int Rev Psychiatry 19:417–427. Ranganath C, Minzenberg MJ, Ragland JD. 2008. The cognitive neuroscience of memory function and dysfunction in schizophrenia. Biol Psychiatry 64:18–25. Reichenberg A, Caspi A, Harrington H, Houts R, Keefe RS, Murray RM, Poulton R, Moffitt TE. 2010. Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: A 30-year study. Am J Psychiatry 167:160–169. Romon T, Mengod G, Adell A. 2011. Expression of parvalbumin and glutamic acid decarboxylase-67 after acute administration of MK801. Implications for the NMDA hypofunction model of schizophrenia. Psychopharmacology (Berlin) 217:231–238. Rueckemann JW, DiMauro AJ, Rangel LM, Han X, Boyden ES, Eichenbaum H. 2015. Transient optogenetic inactivation of the medial entorhinal cortex biases the active population of hippocampal neurons. Hippocampus 26:2462260. Smith DM, Barredo J, Mizumori SJ. 2012. Complimentary roles of the hippocampus and retrosplenial cortex in behavioral context discrimination. Hippocampus 22:1121–1133. Sohal VS, Zhang F, Yizhar O, Deisseroth K. 2009. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459:698–702. Tamminga CA, Stan AD, Wagner AD. 2010. The hippocampal formation in schizophrenia. Am J Psychiatry 167:1178–1193. Tanaka KZ, Pevzner A, Hamidi AB, Nakazawa Y, Graham J, Wiltgen BJ. 2014. Cortical representations are reinstated by the hippocampus during memory retrieval. Neuron 84:347–54. Tendolkar I, Weis S, Guddat O, Fernandez G, Brockhaus-Dumke A, Specht K, Klosterk€otter J, Reul J, Ruhrmann S. 2004. Evidence for a dysfunctional retrosplenial cortex in patients with schizophrenia: A functional magnetic resonance imaging study with a semantic-perceptual contrast. Neurosci Lett 369:4–8. Tort AB, Rotstein HG, Dugladze T, Gloveli T, Kopell NJ. 2007. On the formation of gamma-coherent cell assemblies by oriens

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lacunosum-moleculare interneurons in the hippocampus. Proc Natl Acad Sci U S A 104:13490–13495. Van Groen T, Wyss JM. 2003. Connections of the retrosplenial granular b cortex in the rat. J Comp Neurol 463:249–263. Vann SD, Aggleton JP. 2002. Extensive cytotoxic lesions of the rat retrosplenial cortex reveal consistent deficits on tasks that tax allocentric spatial memory. Behav Neurosci 116:85–94. Vann SD, Aggleton JP. 2004. Testing the importance of the retrosplenial guidance system: effects of different sized retrosplenial cortex lesions on heading direction and spatial working memory. Behav Brain Res 155:97–108. Vann SD, Aggleton JP, Maguire EA. 2009. What does the retrosplenial cortex do? Nat Rev Neurosci 10:792–802. Vazdarjanova A, Guzowski JF. 2004. Differences in hippocampal neuronal population responses to modifications of an environmental context: Evidence for distinct, yet complementary, functions of CA3 and CA1 ensembles. J Neurosci 24:6489–6496. Vazdarjanova A, McNaughton BL, Barnes CA, Worley PF, Guzowski JF. 2002. Experience-dependent coincident expression of the effector immediate-early genes Arc and Homer 1a in hippocampal and neocortical neuronal networks. J Neurosci 22:10067210071. Wesierska M, Dockery C, Fenton AA. 2005. Beyond memory, navigation and inhibition: Behavioural evidence for hippocampus-dependent cognitive coordination in the rat. J Neurosci 25:2413–2419. Wesierska M, Adamska I, Malinowska M. 2009. Retrosplenial cortex lesion affected segregation of spatial information in place avoidance task in the rat. Neurobiol Learn Mem 91:41–49. Wilson MA, McNaughton BL. 1993. Dynamics of the hippocampal ensemble code for space. Science 261:1055–1058. Wulff P, Ponomarenko AA, Bartos M, Korotkova TM, Fuchs EC, Bahner F, Both M, Tort AB, Kopell NJ, Wisden W, Monyer H. 2009. Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons. Proc Natl Acad Sci U S A 106:3561–3566. Wyss JM, Van Groen T. 1992. Connections between the retrosplenial cortex and the hippocampal formation in the rat. Hippocampus 2: 1–11. Zhang ZJ, Reynolds GP. 2002. A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55:1–10.

Hippocampus

Acute systemic MK-801 induced functional uncoupling between hippocampal areas CA3 and CA1 with distant effect in the retrosplenial cortex.

The hippocampus and retrosplenial cortex are integrated within a higher-order cognitive circuit supporting relational (spatial, contextual, episodic) ...
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