Animal models recapitulating the multifactorial origin of Tourette syndrome.

CHAPTER EIGHT

Animal Models Recapitulating the Multifactorial Origin of Tourette Syndrome Simone Macrì*,1, Martina Proietti Onori*,1, Veit Roessner†, Giovanni Laviola*,2

*Section of Behavioural Neuroscience, Department Cell Biology and Neuroscience, Istituto Superiore di Sanita`, Roma, Italy † Department of Child and Adolescent Psychiatry, Technical University Dresden, Dresden, Germany 1 S. M. and M. P.O. equally contributed to the chapter. 2 Corresponding author: e-mail address: [email protected]

Contents 1. Tic Disorders and Tourette Syndrome 2. Tourette Syndrome: Etiological Factors 2.1 Genetic factors 2.2 Environmental factors 3. Animal Models of TS 3.1 Transgenic animal models 3.2 Immune-mediated animal models 3.3 Stress paradigms mimicking psychosocial stress in mice 4. Future Perspectives Acknowledgments References

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Abstract Tourette Syndrome (TS) is a neurological disorder characterized by motor and phonic tics affecting approximately 1% of the pediatric population. Behavioral comorbidities often include obsessive–compulsive behavior and impaired attention. The neurobiological substrates associated with TS generally entail abnormalities in neurotransmitter circuitry regulating basal ganglia activity. The neurotransmitters most often associated with TS are dopamine, serotonin, and GABA. TS origin roots in genetic predisposing factors, and environmental variables favoring tic onset and exacerbation. Among the latter, repeated infections with group A beta-hemolytic Streptococcus and psychosocial stressors encountered during development have been proposed to constitute likely susceptibility factors. In this chapter, we describe how this clinical/epidemiological knowledge has been translated into animal models of TS. Specifically, we review several studies attempting to reproduce TS-like symptoms (tics and behavioral stereotypies) and comorbidities (impaired attention, increased locomotion, and perseverative

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responding) in laboratory rodents. Additionally, we discuss studies in which the genetic and environmental predisposing factors have been modeled in experimental subjects. Ultimately, we propose a unifying perspective recapitulating dependent and independent variables in the preclinical study of TS and discuss its potential theoretical and heuristic implications.

1. TIC DISORDERS AND TOURETTE SYNDROME Tics are defined as nonrhythmic, involuntary, and rapid movements or sounds (American Psychiatric Association, 2000). Most children, approximately 15%, experience during their development a transient tic condition, not requiring medical treatment, with one or few tics that disappear within less than 1 year (Robertson, 2008). The severity and course of the expression of tics differentiate the transient tic condition from the chronic tic disorder in which the motor or vocal tics are present for more than 1 year (Kurlan et al., 2001). Tourette Syndrome (TS) is diagnosed when both chronic motor and phonic tics are expressed for more than 1 year (Swain, Scahill, Lombroso, King, & Leckman, 2007). TS is a neuropsychiatric disorder with a childhood onset that is estimated to mainly affect prepubertal boys (Leckman, Bloch, Smith, Larabi, & Hampson, 2010). Its prevalence in the pediatric population ranges between 0.4% and 1%. TS symptoms fluctuate over time in frequency and intensity, reach a peak in severity between 10 and 14 years of age and tend to dissipate during late adolescence or early adulthood (Leckman, 2012). Additionally, affected children may experience comorbid symptoms that characterize other neurobehavioral manifestations, including attentiondeficit hyperactivity disorder (ADHD) and obsessive–compulsive disorder (OCD), such as aggressiveness, emotional liability, affective disorders, and compulsive behaviors (Cohen, Leckman, & Bloch, 2013; Lombroso & Scahill, 2008). Different environmental variables may influence the waxing and waning course of tics. Specifically, psychosocial stressors, anxiety, and emotional tension may exacerbate the expression of tics (Hoekstra, Dietrich, Edwards, Elamin, & Martino, 2013). In most cases, affected individuals are able to exert a voluntary cognitive control over the expression of tics, but after a period of suppression tics may even become more uncontrollable and disabling (Jung, Jackson, Parkinson, & Jackson, 2012). Furthermore, shortly before the expression of tics, patients describe a restless feeling of discomfort, a “premonitory urge” experienced in the body’s area where the tic is about to occur (Bliss, 1980; Jankovic & Kurlan, 2011; Leckman et al., 2010).

Animal Models of Tourette Syndrome

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2. TOURETTE SYNDROME: ETIOLOGICAL FACTORS Several studies (neuroimaging, neurophysiological, and postmortem analyses on brain tissues) identified functional and anatomical abnormalities in brains of TS patients at the level of the circuitry connecting the basal ganglia to the cerebral cortex (Berardelli, Curra`, Fabbrini, Gilio, & Manfredi, 2003; Singer & Minzer, 2003). The basal ganglia, which include the striatum, the subthalamic nucleus, and the globus pallidus, play a significant role in the regulation of the cortex excitability and in the selection of movements through the involvement of different neurotransmitter systems. In particular, the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has a prominent role in the functioning of the striatum and globus pallidus, in conjunction with a modulatory role played by dopamine projections from the substantia nigra, located in the midbrain, to the striatum (Ganos, Roessner, & Mu¨nchau, 2013). The efficacy of specific medical treatments for the reduction of tics and the use of pharmacological animal models (see Section 3) focused the attention on the involvement of specific neuromodulatory systems on the emergence of tics (Bronfeld, Israelashvili, & Bar-Gad, 2012). Evidence for a causal relationship between dopamine dysfunction and TS pathophysiology came from the finding that the use of antipsychotic drugs (pimozide and haloperidol) acting as antagonists on D2 receptors reduces the expression of tics. Furthermore, an excess of nigrostriatal activity has been found in TS patients (Albin et al., 2003) with increased levels of D2 receptors and DA transporter (DAT) levels (Cheon et al., 2004; Wolf et al., 1996). The dopaminergic pathway and other neurochemical systems are modulated by the noradrenergic system located in the brain stem, mainly in the locus coeruleus, and innervating all central nervous system regions (Foote, Bloom, & Aston-Jones, 1983). Alpha 2-adrenergic agonists have been found to exert positive effects on tic suppression, suggesting that a hyperadrenergic system may be associated with TS (Arnsten, 2001; Arnsten & Pliszka, 2011). However, a systematic metaanalysis revealed that the efficacy of Alpha 2-adrenergic agonists in mitigating TS symptoms may depend on the presence of comorbid symptoms. Thus, Alpha 2 adrenergic agonists were particularly beneficial only in the presence of comorbid ADHD symptoms (Weisman, Qureshi, Leckman, Scahill, & Bloch, 2013). Most treatments affecting serotonin functions have not shown significant results (Scahill et al., 1997) even though patients have been found to have lower plasma levels of tryptophan (the precursor of serotonin in the

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biosynthetic pathway) than normal and some postmortem studies have shown reduced brain tryptophan concentrations (Comings, 1990).

2.1. Genetic factors Several studies supported the hypothesis that TS is an inherited developmental disorder of neurotransmission. Prevalence of TS in first-degree relatives ranges between 5% and 15% (O’Rourke, Scharf, Yu, & Pauls, 2009). Furthermore, genetic studies show that the ratio of concordance in monozygotic versus dizygotic twin pairs is approximately 5:1 (Price, Kidd, Cohen, Pauls, & Leckman, 1985). Previous data supported the hypothesis of a single major autosomal dominant gene with pleiotropic expression (i.e., chronic motor tics, TS, or OCD) and incomplete penetrance (about 70% in women, 99% in men; Pauls, 1992). Recent linkage methods and analyses of families with visible chromosomal abnormalities are currently used to decipher the genetic contribution to TS (Deng, Gao, & Jankovic, 2012). Several candidate susceptibility genes are emerging from clinical studies of chromosomal aberrations. For example, the disruption of the IMMP2L (inner mitochondrial membrane peptidase 2 like) gene, due to a translocation breakpoint on the chromosome 7, has been identified in one isolated and one familial case of TS, providing evidence for a role of this gene in the pathogenesis of TS (Patel et al., 2011; Petek et al., 2001). Particular attention has been dedicated to members of cell-adhesion molecules at nerve cell synapses. In this framework, a mutation in the X-linked gene neuroligin4 (NLGN4X) has been discovered in a family with various developmental disorders (autism, ADHD, and TS) (Lawson-Yuen, Saldivar, Sommer, & Picker, 2008) and a truncation in the region of the CNTNAP2 gene has been found in a family with TS (Verkerk et al., 2003). The CNTNAP2 is a gene encoding Caspr2 (contactin-associated protein-like 2), a member of the neurexins superfamily localized to the juxtaparanodal regions of myelinated axons and involved in the correct positioning of the Shaker-type voltage-activated Kþ channels (Poliak et al., 1999). The expression of tics in TS patients may be related to the influence of this mutation in the conduction and repolarization of action potentials in specific brain regions, specifically in striatal circuits and in the frontal cortex of the adult human brain, where the messenger of CNTNAP2 is particularly enriched (Abrahams et al., 2007). Nevertheless, disruption of CNTNAP2 does not necessarily lead to the symptoms of TS (Belloso et al., 2007), giving more validity to the likely polygenic character of the syndrome.


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Two different mutations have been found in a member of the SLIT and TRK family of proteins, SLITRK1, in TS patients: a deletion that led to a truncated form of the protein and a missense mutation in the 30 -untranslated region of the gene (Abelson et al., 2005; Proenca, Gao, Shmelkov, Rafii, & Lee, 2011). This protein is involved in neurite outgrowth and branching (Kajiwara, Buxbaum, & Grice, 2009; Linhoff et al., 2009) and is expressed in the cortex, thalamus, and basal ganglia, reflecting the circuit most commonly implicated in TS (Stillman et al., 2009). Interestingly, the finding of a single rare coding mutation in the gene encoding the rate-limiting enzyme in the biosynthetic pathway of histamine, the L-histidine decarboxylase (HDC) gene, led to the hypothesis of a possible involvement of histaminergic pathway in the pathogenesis of TS (Ercan-Sencicek et al., 2010). The G protein-coupled receptor for histamine, H3R, is highly enriched in the striatum of rodents and humans and regulates both dopamine and serotonin actions (Haas, Sergeeva, & Selbach, 2008). A recent study by Karagiannidis et al. (2013) partly supported the histaminergic hypothesis through the analysis of variations across the HDC gene in a large sample of familiar cases of TS. In this study, the authors observed an over-transmission of two single nucleotide polymorphisms in the HDC gene associated with TS (Karagiannidis et al., 2013).

2.2. Environmental factors Recent observations suggest that TS may have a multifactorial nature in which environmental factors in interaction with the polygenic background (Seuchter et al., 2000) may contribute to the onset of the pathology (State, 2011). Prenatal environmental risk factors (such as perinatal hypoxic/ischemic events, prenatal maternal smoking, low birth weight, and maternal stress) may exert an organizational role in the development and functioning of brain pathways thought to be relevant for the emergence of tics (Hoekstra et al., 2013). Studies involving affected monozygotic twins revealed that the twin that suffered perinatal complications had a higher intensity in tic severity (Randolph, Hyde, Gold, Goldberg, & Weinberger, 1993). Beside prenatal factors, postnatal environmental factors may affect the activity of neurons in crucial brain regions, possibly relating to the fluctuation in tic severity. More recently, streptococcal infections have been proposed as an additional environmental factor potentially favoring the production of tics through immune-mediated mechanisms (Cardona & Orefici, 2001). Martino et al. (2011) systematically addressed this hypothesis in a cohort study. Although the authors observed that infections did not

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predict exacerbations in tic severity, they observed an increased susceptibility to streptococcal infections in TS patients. In several cases, tics began suddenly after a streptococcal infection, thus leading to the proposal of a working hypothesis explaining pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS; Swedo et al., 1998). The proposed definition criteria for PANDAS are: (1) prepubertal onset, (2) the presence of chronic tic disorders or OCD, (3) a relapsing–remitting course, (4) clinical evidence of Group A Streptococcus (GAS) infection associated with onset or exacerbation of tics, (5) association with neurological abnormalities such as a reduced motor coordination or motor hyperactivity (but not chorea). It is important to notice that defining criteria for PANDAS are still highly debated and under constant reappraisal. Despite the potential role attributed to streptococcal infections in modulating TS symptoms, the precise relationship between such infections, antineuronal antibodies, and TS remains elusive. Such working hypothesis is currently under investigation in several initiatives including a pan-European research project (http://www.emtics.eu). GASinduced antibodies directed against different epitopes in the basal ganglia have been detected in some cases of TS (Kiessling et al., 1993, 1994; Martino & Giovannoni, 2004; Singer et al., 1998), thereby strengthening the hypothesis of an immune or autoantibody-mediated mechanism. In other cases, the link between GAS infections and TS has not been detected (Kawikova et al., 2010; Martino et al., 2011; Singer, Gause, Morris, & Lopez, 2008) and the levels of autoantibodies in patients’ sera have been found equivalent to the levels of controls (Kawikova et al., 2010; Morris, Pardo-Villamizar, Gause, & Singer, 2009; Singer, Hong, Yoon, & Williams, 2005). Mimicry models have been proposed to explain the autoantibody-mediated mechanism, one involving a cross-reactivity between a carbohydrate domain of the bacterial cell wall and brain lysoganglioside GM1 and another involving cross-reactivity between streptococcal and neuronal isoforms of glycolytic enzymes (Dale et al., 2006). Some observations support a connection between GAS infection and tics. Children with TS have altered immunoregulatory mechanisms (such as reduced numbers of regulatory T cells and abnormal cytokine secretion) which may predispose to autoimmune responses to GAS and/or may predispose to a higher number of GAS infections (Hornig & Lipkin, 2013). In a large case–control study, children with OCD or a chronic tic disorder were twice as likely as controls to have had a documented GAS infection in the 3 months prior to the neuropsychiatric diagnosis, and children with multiple GAS infections in


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the preceding year were more likely to be diagnosed with TS than children who did not encounter multiple infections (Mell, Davis, & Owens, 2005). However, independent investigators failed to replicate these findings, whereby a clear association between streptococcal infections and TS symptoms was not observed (Schrag et al., 2009). Yet, the limited statistical power of this study does not allow unequivocal conclusions. Furthermore, several patients with either tics or OCD have been found to have high levels of antistreptococcal circulating antibodies directed against neuronal components (Kiessling et al., 1993; Wendlandt, Grus, Hansen, & Singer, 2001). The complexity of TS etiology is increased by the clinical observation that TS patients seem to be more sensitive to psychosocial stress than normal subjects (Chappell et al., 1994; Conelea & Woods, 2008; Corbett, Mendoza, Baym, Bunge, & Levine, 2008). Children with TS show a higher reactivity of the hypothalamic–pituitary–adrenal (HPA) axis resulting in a significant elevation of corticotropin-releasing factor and cortisol in response to stressful events (Conelea, Woods, & Brandt, 2011; Corbett et al., 2008). GAS infections and psychosocial stress have been proposed to interact with immune and endocrine systems in creating a neurobiological vulnerability to tics (Lin et al., 2010).

3. ANIMAL MODELS OF TS In line with the aforementioned genetic and environmental hypotheses, several scholars attempted to develop suitable animal models recapitulating TS phenotypic abnormalities and etiological factors. While hardly ever do laboratory rodents exhibit tics, several abnormal spontaneous or pharmacologically induced movements expressed by animals have been considered indicators of TS-like symptoms. The theoretical rationale for the analysis of these manifestations can be traced back to the concepts of face and construct validities. While the former relates to the phenomenological similarity between human symptoms and animal model, the latter is an indicator of the correspondence between the etiological factors precipitating the disease in humans and in the animal model. Ultimately, the behavioral analysis of rodent models of TS attempted to address symptoms that (i) are highly similar to tics, (ii) depend on a dysfunction of the neurotransmitter systems potentially involved in the etiology of TS, (iii) closely resemble symptoms that characterize frequent comorbidities. Within this framework, several authors identified specific behavioral manifestations analogous to tics. These behavioral patterns generally manifest as jerk-like movements or brief and

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0.0 s

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Figure 8.1 Still-frame sequence of a body-jerk response induced by the administration of the selective 5HT2A receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine).

repetitive twitching performed at low frequency during grooming behavior (Tse & Wei, 1986). A rapid increase in head twitch and body-jerk (Fig. 8.1) responses, highly isomorphic to tics, has been described in response to the administration of drugs that increase serotonergic activity (Canal & Morgan, 2012). An analogous pharmacological modulation has been leveraged through the use of substances affecting neurotransmitter systems within the cortico-striatal circuitry, as GABAa (McKenzie, Gordon, & Viik, 1972; Patel & Slater, 1987) and dopamine (Dantzer, 1986). These substances have been shown to induce abnormal behaviors similar to those induced by serotonergic drugs (Dursun & Handley, 1992). Behavioral stereotypies, apparently purposeless repetitive movements, are also generally ascribed to a dysfunction of the basal ganglia. Therefore, they often constitute a relevant parameter in the analysis of putative mouse models of TS. Ultimately, several studies attempted to investigate behavioral and cognitive domains frequently affected in comorbid disturbances as ADHD and OCD. Within this framework, attentional set-shifting abilities and hyperlocomotion may constitute relevant outcome measures. The validity of these behavioral patterns as indicators of TS-like abnormalities has already been detailed elsewhere (Macrı`, Proietti Onori, & Laviola, 2013).

3.1. Transgenic animal models Beside the pharmacological induction of behaviors resembling the symptomatology, several attempts have been made to reproduce the genetic


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predispositions that may favor the onset and progression of the pathology. Mutations in genes known to be involved in the disorder, null mutations as well as mutations which alter but do not eliminate gene function, can be introduced in the mouse genome by means of gene targeting procedures. The aim is to replicate, as far as possible, the symptoms according to the genetic etiological factors proposed for the disease (construct validity). Susceptibility genes related to neurotransmitter systems involved in the cortico-striatal circuit have been studied through different engineered rodent models (Paschou, 2013). Specifically, various dopamine receptors (Comings et al., 1991; Lee et al., 2005) and the dopamine transporter gene (DAT1) (Dıáz-Anzalduá et al., 2004) have been investigated for association with TS. According to the “dopamine hypothesis” for TS (Buse, Schoenefeld, Mu¨nchau, & Roessner, 2013), based on the idea of an excess nigrostriatal dopaminergic activity (Singer, Butler, Tune, Seifert, & Coyle, 1982), a mutant mouse model of hyperdopaminergic activation (DAT knockdown) has been developed (Zhuang et al., 2001). These mice exhibit elevated levels of extracellular DA in the neostriatum and tend to be hyperactive and show excessive body grooming (an activity in which the animal, usually in sitting position, licks its fur and grooms with the forepaws). Interestingly, the excessive locomotor activity is alleviated by the administration of psychostimulants (Robertson & Feng, 2011). Though not equivalent to tics, abnormal repetitive grooming constitutes a motor stereotypy associated with dysfunctions at the level of the basal ganglia (Garner & Mason, 2002; Gross, Richter, Engel, & Wu¨rbel, 2012). Ultimately, abnormalities in grooming may provide relevant information regarding the neurobiology of tics. Greer and Capecchi (2002) described an excessive grooming behavior in Hoxb8 homozygous mutant mice resulting in remarkable hair pulling (Greer & Capecchi, 2002). The Hoxb8 gene encodes a nuclear protein which binds DNA sequences, expressed in multiple brain regions including the orbitofrontal cortex and the limbic system (Huber, Ferdin, Holzmann, Stubbusch, & Rohrer, 2012). In the light of the compulsive grooming and hair removal, these mice have been proposed as a potential model for the study of OC-spectrum disorders, which represent a common comorbidity of TS (Chen et al., 2010). Alzghoul et al. (2012) recently developed a genetically engineered mouse model exhibiting a reduction in the levels of functional MAO-A enzyme, involved in the degradation of monoamine neurotransmitters. These engineered mice show high levels of serotonin (5-HT) and noradrenaline

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(NA) in the hippocampus, in motor and prefrontal cortex, and in the striatum (Alzghoul et al., 2012; Bortolato et al., 2011). They exhibit reduced motor coordination and balance, reflecting the morphological abnormalities found in the cerebellum. The disruption of the monoamine systems could alter the circuitry connecting the cerebellum with the fronto-striatal basal ganglia region, resulting in motor deficits. These mice also express perseverative behaviors, potential endophenotypes for the study of some neurodevelopmental disorders, including autism-spectrum disorder and TS (Bortolato, Chen, & Shih, 2008). To gain further insights regarding the potential role of the histaminergic transmission, HDC-null mice have been recently developed and constitute a promising research avenue. Even though only partially do HDC-null models recapitulate TS symptomatology, they show decreased histamine levels and a significant increase of stereotypic behaviors upon administration of DA agonists, compared to wild-type mice (Kubota et al., 2002). A high degree of face and construct validity (Van Der Staay, Arndt, & Nordquist, 2009) has been reached with the transgenic mouse model (D1CT-7) developed by Nordstrom and Burton (2002). It expresses two hyperactive groups of neuronal populations in the adult CNS, a glutamatergic neuronal population and a population of GABAergic interneurons (Campbell, McGrath, & Burton, 1999). The D1CT-7 mouse model exhibits TS-like symptoms, including very brief (0.05–0.1 s) isolated head and body jerk or shake resembling human tics. The use of the Alpha 2-noradrenergic agonist clonidine, a commonly used treatment for the reduction of tics in humans (Nordstrom & Burton, 2002), supports the predictive validity of the model, defined as the degree of correspondence between the clinical efficacy of the treatment in human and animals (Korff & Harvey, 2006). Based on the clinical evidence of sequence variants in Slitrk1 gene associated with TS (Proenca et al., 2011), Katayama et al. (2010) developed a Slitrk1-knockout model and analyzed the behavioral and neurochemical abnormalities associated with the loss of this gene. The behavioral results show that these transgenic mice exhibit elevated anxiety-like and depressive-like behaviors. Specifically, in the elevated plus-maze, an approach-avoidance test in which rodents are faced with the possibility of exploring two protected and unprotected arms, they spend less time in the open arms, compared to control mice (the latter being considered an index of anxiety) (Pellow, Chopin, File, & Briley, 1985); in the forced swimming test (the mouse is placed in a tall cylinder filled with water where


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it swims seeking an escape route) and in the tail suspension test (the mouse is suspended by its tail and struggles to reach a solid surface), the percentage of time spent in immobility, considered as an index of a depressive-like state, is increased (Katayama et al., 2010). The authors show that the administration of clonidine, such as for the D1CT-7 mouse model, attenuates the increased anxiety-like behavior. The efficacy of clonidine suggests an involvement of the noradrenergic pathways in TS (Kang, Zhang, Jiao, Guo, & Gao, 2009; Leckman et al., 1991). Even though slitrk1-deficient mice do not exhibit any motor stereotypies or tic-like symptoms, neurochemical analyses unveil an alteration in the noradrenergic system with high levels of NA and its metabolite (MHPG) in the prefrontal cortex, striatum, and nucleus accumbens of transgenic mice. These observations, together with a clear genetic hypothesis derived from clinical evidence, beget this model an elevated degree of validity.

3.2. Immune-mediated animal models The heterogeneity of TS pathology makes it likely that environmental risk factors may contribute to the emergence and/or progression of the disorder acting on genetically vulnerable individuals. Within this context, animal models provide the opportunity to clarify the contribution of streptococcal infections to the progression and severity of the pathology. Different immune-mediated animal models of TS have been produced leveraging a variety of strategies. Some of them involve the exposure to immune mediators, such as proinflammatory cytokines (IL-1b and TNF-a), that alter the function of neural pathways relevant to TS; other approaches are based on the immunization with immunogenic microbial components that are thought to cross-react with endogenous targets. Furthermore, sera derived from actively immunized animals or from affected patients can be transfected into naı¨ve animals with the aim of inducing a disruption in the CNS signaling and studying its behavioral consequences (Hornig & Lipkin, 2013). The first line of studies infused directly the serum of patients with antineuronal antibodies into rodent striatum (Hallett, Harling-Berg, Knopf, Stopa, & Kiessling, 2000; Taylor et al., 2002). These studies demonstrated that the infusion of sera from TS patients induced stereotypic movements and the presence of IgG deposits in rats. Furthermore, they were useful to detect whether distinct isotypes of Ig were capable of inducing striatal dysfunctions in vivo, although they did not allow the identification of the etiologic factors responsible for the generation of autoantibodies. A promising approach is constituted by the use of preclinical animal

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models exposed to passive transfer immunization protocols. These studies entail the active immunization of subjects through streptococcal antigens. Such immunization readily results in the production of antibodies, which are then passively transferred to naı¨ve mice (e.g., Yaddanapudi et al., 2010). This approach is functional to understanding the role of antibodies in mediating the effects of Streptococcus regardless of a general unspecific activation of the immune system. 3.2.1 Experimentally induced increment in brain immune mediators Different studies have shown that the peripheral administration of immune mediators such as cytokines and soluble cytokine receptors can alter the development of the CNS leading to persistent behavioral changes, such as motor stereotypies and abnormal repetitive behaviors (Zalcman, Murray, Dyck, Greenberg, & Nance, 1998; Zalcman, Patel, Mohla, Zhu, & Siegel, 2012). Specifically, different cytokines affect the function of distinct brain monoaminergic systems. For example, the administration of IL-2 to male BALB/c mice influences the release of DA in mesocorticolimbic structures while IL-6 also affects the activity of 5-HT (Zalcman et al., 1994, 1998). A series of behavioral domains appear to be affected. Prenatal treatments that involved the exposure of mice to IL-2 and IL-6 cytokines led to long-lasting immune and behavioral dysfunctions in the offspring of mice (Ponzio, Servatius, Beck, Marzouk, & Kreider, 2007; Smith, Li, Garbett, Mirnics, & Patterson, 2007). These studies demonstrated that the exposure to increased levels of cytokines during plastic stages of brain development might cause immunological alterations and behavioral disturbances (increased grooming and rearing) that represent a core characteristic of TS. It has been proposed that increased cytokine exposure during key periods of brain development as a consequence of early life infections may act as a “sensitizing” factor altering the way the brain responds to later-life immune challenges (Bilbo & Schwarz, 2009). Microglial cells have been proposed as the suitable target for the long-term changes occurring within the brain in consequence of neonatal infections (Bilbo et al., 2005). Microglia represent the immunocompetent cells of the brain that, in response to immune stimulation, become active and produce cytokines and chemokines to recruit immune cells into the brain. Early infections during critical periods of brain development may induce a change in microglia cells (glial priming). Primed microglial cells will overproduce cytokines in response to a future immune challenge compared to normal microglial cells that were not sensitized (Perry, Newman, & Cunningham, 2003).


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3.2.2 Animal models based on immunization with microbial immunogens The peripheral exposure of rodents to microbial antigens allows the study of the mechanisms involved in the induction of autoantibodies putatively associated to the etiology of TS. The same experimental approach may provide useful information regarding the process through which immune molecules access the brain by crossing the blood–brain barrier (BBB). Peripherally generated antibodies and immune molecules usually do not cross the BBB (Willis, 2012). A chronic exposure to cytokines, stressful events, and infection can compromise the BBB integrity, thereby facilitating the immune molecules entry into the brain (Mas´li nska, 2001). It has been also hypothesized that they can use an active transport mechanism to cross the BBB. Hoffman, Hornig, Yaddanapudi, Jabado, and Lipkin (2004) observed that female SJL/J mice (a strain with a high propensity to show autoimmune responses), actively immunized with GAS homogenate, exhibited some behavioral abnormalities reminiscent of TS that satisfy some of the criteria for PANDAS (Hoffman et al., 2004). Specifically, these mice show a spectrum of behavioral abnormalities (increased rearing behavior, compulsive grooming, and decreased motor coordination) that correlate with an elevation in titers of antibodies cross-reacting with cell bodies of neurons within the mouse cerebellum, globus pallidus, and thalamus. A subsequent study by the same research group reproduced the key aspects of the previous model (Yaddanapudi et al., 2010). In this case, naı¨ve mice, passively immunized with GAS sera derived from actively immunized mice, exhibited behavioral dysfunctions similar to those exhibited by donor mice (increased rearing and passive social behaviors). Yet, these mice failed to show any alteration in motor coordination. Furthermore, the observation that IgG-depleted GAS sera did not produce the same effect indicates that IgG is the active, key component in the induction of behavioral abnormalities. The principal difference between donor and recipient mice was found in the localization of the IgG deposits in brain. In fact, while IgG deposits in the brains of donor mice were found within the cerebellum, globus pallidus, and thalamus, IgG deposits in recipient mice were confined to neurons in the hippocampus and periventricular area. This could be correlated with the use of different substances used to disrupt the integrity of the BBB (Freund’s adjuvant in the first case and LPS in the passive transfer) (Kerr, Krishnan, Pucak, & Carmen, 2005). Similar findings were obtained with a rat model of PANDAS in which experimental subjects were immunized with a cell-wall antigen preparation

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of GAS M protein type 18 bacteria as immunogen (in contrast with M protein type 6 used by Hoffman and colleagues). Male Lewis rats exposed to GAS exhibited a behavioral profile and an immunological response phenotype that was similar to that shown by mice exposed to active immunization with GAS (Hoffman et al., 2004). Specifically, motor disturbances (impaired manipulation of food and inability to traverse a narrow beam) were observed along with an increase in induced-grooming behavior that might represent a form of compulsive activity, consistent with the compulsive and obsessive symptoms found in the clinic for PANDAS cases (Brimberg et al., 2012). These symptoms were alleviated by the administration of haloperidol (DR2 antagonist) and paroxetine (SSRI), respectively, used to alleviate motor and compulsive symptoms. As previously demonstrated by Hoffman et al. (2004), this study further supports a causal relationship between the exposure to GAS and the development of behavioral disorders underlined by the detection of IgG deposits in the striatum, thalamus, and frontal cortex. In addition, Brimberg et al. (2012) revealed that exposure to GAS resulted in alteration in the glutamatergic and dopaminergic systems, with lower glutamate content and increased levels of DA in the frontal cortex and entopeduncular nucleus. Furthermore, this new model demonstrates that antistreptococcal rat sera (IgG) from GAS-exposed rats react significantly with human dopamine receptor D1 and D2, as detected in sera from children with PANDAS and Sydenham’s chorea (Brimberg et al., 2012). These findings further suggest a role for a dysfunctional cortico-striatal pathway in the induction of behavioral abnormalities, as hypothesized from clinical evidence (Felling & Singer, 2011).

3.3. Stress paradigms mimicking psychosocial stress in mice To investigate the interaction among TS predisposing factors and psychosocial stressors, it is tenable to combine the aforementioned disease models with paradigms imposing variable degrees of stress to laboratory rodents. This aim has been achieved through a plethora of ad hoc developed stimuli and paradigms. A preliminary distinction between these paradigms may rest on the dissociation between chronic and acute stressors. Chronic stressors entail repeated exposures to mild challenges, such as electric shock, water immersion, or restraint. Yet, these models have been criticized based on the following ground: first of all, the perceived relative intensity of a given stressor is both species- and strain-dependent; furthermore, the timing and definition of “chronic” varies across studies, ranging from 2 to 16 h per day


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applied over a period of 7–28 days (Schmidt et al., 2007); therefore, some authors questioned the chronic nature of these models as the stressors are only applied for a relatively short time per day or for only a few consecutive days. Finally, laboratory rodents may display habituation to predictable and repeated stressful stimuli, thereby showing reduced psychophysiological responses to the same challenge. To address this potential shortcoming, Willner (2005) devised the chronic mild stress procedure. The latter is characterized by different types of mild stressors presented in a randomized order: this strategy is aimed at minimizing habituation and predictability. A potential limitation for the exploitation of these models to the study of TS is that the latter is favored by social stress. Thus, one major drawback of these rodent stress paradigms is their weak consideration of social stress (Heinrichs & Gaab, 2007). To overcome this limitation, and mimic constant social stress, it is possible to leverage the highly social nature of laboratory rodents altering their housing conditions. Specifically, it is possible to expose laboratory rodents to the visual, olfactory, and nontactile presence of a dominant individual in the home cage (Bartolomucci et al., 2005). The latter has been proposed to constitute one of the most pervasive stressors (Bartolomucci et al., 2005; Fuchs, 2005). There is a large body of evidence indicating that long exposure to social stressors may remarkably influence the activity of the HPA axis and relate to a high “mortality rate” in animals (Fuchs, 2005). Closely related, there is also a large body of evidence from rodent studies indicating a link between chronic or repeated stress and immunological dysfunctions (Nyuyki, Beiderbeck, Lukas, Neumann, & Reber, 2012; Schmidt et al., 2010). As also discussed earlier, the interaction between an altered regulation of the HPA axis and immune system may constitute predisposing factors for TS. Additionally, to further confirm the relevance of chronic stress paradigms within the field of TS, several studies demonstrated that experimental procedures interfering with the regulation of the HPA axis also altered dopaminergic activity. We recently discussed the interaction between TS and dopaminergic system in an independent paper (Buse et al., 2013). Alternative social stress paradigms in rodents have been developed: for example, the sensory contact model (Kudryavtseva, 1991), the chronic subordinate colony housing (Reber et al., 2007) and the social defeat paradigm in mice (Ader, 1969), or the visible burrow system in rats (Blanchard et al., 1995). The feasibility of these paradigms may be limited by the extensive need of man power, space, and time. All these aspects limit the number of animals per group that can be studied at a time. Reduced group size may hamper experimental validity due to the following aspects: (1) elevated

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interindividual variability in susceptibility to chronic stress and stressinduced symptoms: this may be due to genetic or epigenetic mechanisms and is remarkably elevated both within (Holmes, 2008) and between strains (Zhang-James, Middleton, & Faraone, 2013); (2) specific timing of stress procedures: the age at which the subject is exposed to chronic stress (e.g., in utero, infantile stage, adolescence, adulthood) is of high importance as there are strong indications that individual vulnerability to stress varies across development (Blanchard, McKittrick, & Blanchard, 2001); (3) also individual differences in circadian rhythmicity have to be considered because the consequences of repeated psychosocial stress are dependent on the time of day of stress exposure (Bartlang et al., 2012); (4) recent studies have indicated that some of the effects evoked by social stressors persist even if the stress is discontinued (Sterlemann et al., 2008) and that there is a large dynamic range in the adaptive plasticity of the brain, allowing the animals to adapt behaviorally and physiologically to the previously occurred stressful situation with the progression of time (Buwalda et al., 2005); (5) specific housing conditions may influence the consequences of chronic psychosocial stress in mice. For example, chronic psychosocial stress resulted in persistent deficits in sensorimotor gating (measured by prepulse inhibition) in individually but not in socially housed mice (Adamcio, Havemann-Reinecke, & Ehrenreich, 2009). Both topics are also a matter of debate in the pathophysiology of TS (Buse et al., 2013). Although the aforementioned protocols have been developed with different purposes, some of them directly addressed some of the dependent variables described in the previous sections. For example, we demonstrated that neonatal stress, in the form of corticosterone administration, may persistently modify individual responses in an attentional set-shifting task (Macrı` et al., 2009). Additionally, several authors demonstrated that both prenatal and postnatal stressors may persistently alter behavioral, hormonal, and immune parameters (Kleinhaus et al., 2010; Maccari & Morley-Fletcher, 2007; Morley-Fletcher, Rea, Maccari, & Laviola, 2003). For example, exposure to early life stressors has been shown to relate to an increase in locomotion (Hohmann, Hodges, Beard, & Aneni, 2013). Ultimately, different studies demonstrated that the exposure to stressful environmental conditions may favor the exhibition of behavioral stereotypies (Garner & Mason, 2002; Gross et al., 2012). The expression of cage stereotypies may be the result of the disinhibition of the response selection system represented by the basal ganglia, further supporting the study of abnormal behaviors as potential models of TS-like symptoms (Garner, Meehan, & Mench, 2003).


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4. FUTURE PERSPECTIVES In the previous sections, we described two of the main approaches adopted to reproduce TS etiology in laboratory rodents: one that incorporates mutations in specific genes implicated in the development of TS and the other that focuses on specific environmental factors that can trigger and/or exacerbate the pathology. TS is a complex neurodevelopmental disorder and its heterogeneity emphasizes the importance of combining the genetic and environmental components of this pediatric disease in a unique animal model. Specifically, precocious environmental factors, including obstetric complications, have been suggested to contribute to the onset of TS, affecting the structural organization of the brain networks underlying TS symptomatology (Laviola, Adriani, Rea, Aloe, & Alleva, 2004; Leckman & Peterson, 1993; Leckman et al., 1987, 1990; Marco, Macrı`, & Laviola, 2011). Furthermore, clinical evidence supports the hypothesis that emotional variables (psychosocial stressors, anxiety, and frustration) may exert a short-term influence on the periodical fluctuation of tic expression (Conelea & Woods, 2008; Wood et al., 2003), involving the mediation of the HPA axis and the noradrenergic pathway (Chappell et al., 1994; Corbett et al., 2008). Genetic predisposition in association with environmental contribution is thought to play a primary role in the pathogenesis of the disorder during critical periods of brain development. Rodent models challenged with different stressors and/or insults during highly plastic developmental stages may favor the analysis of the environmental factors leading to neuropsychiatric symptoms (Macrı` et al., 2013; Marco et al., 2011). We offer that future studies on animal models of TS shall combine genetic and/or immune aspects with perinatal exposure to stress. For example, the exposure to gestational stressors in rodents could be used to test the role of maternal stress as a risk factor for Tourette. A number of different manipulations in early life have been demonstrated to affect permanently the course of central nervous system development, including neuroendocrine systems such as the HPA axis. Examples of models of prenatal manipulations include maternal stress, exposure to synthetic glucocorticoids, and nutrient restriction (Liu, Li, & Matthews, 2001; Maccari & Morley-Fletcher, 2007; Weinstock, 2001). Stress during gestation has also been associated with disturbances in the immune system. Adult rats exposed to prenatal stress show a significant reduction in CD4þ T and CD8þ T lymphocytes and circulating anti-inflammatory IL-10 cytokines and a significant increase in proinflammatory cytokine IL-1b,

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suggesting a role for stress hormones in the outcome of various immunemediated diseases (Laviola et al., 2004). The environment can exert its influence during different critical developmental stages, including postnatal period, early infancy, and adolescence. In animal models, some of the postnatal manipulations that can be used to permanently modify HPA axis function are constituted by neonatal handling, maternal deprivation, exposure to glucocorticoids, and infections (Bakker, Van Bel, & Heijnen, 2001; Macrı´, Mason, & Wu¨rbel, 2004; Macrı`, Zoratto, & Laviola, 2011; Meaney et al., 2000; Nilsson et al., 2002). For example, we identified a change in the level of natural antibodies against SERT and DAT proteins (5-HT and DATs, respectively) in serum samples of adult mice exposed to different doses of corticosterone during lactation (Macrı` et al., 2009). Psychosocial stress remains one of the most important contextual factors influencing tic severity and potentially modulating the effect of bacterial infections. The mechanism of this interaction needs further investigation and animal models combining autoimmune hypothesis with exposure to developmental stress may constitute a promising research avenue. So far, most of the TS-like symptoms have been modeled in late adolescent/fully adult rodents. We believe that a particular emphasis to the timing of the onset of the symptoms relevant for TS would be necessary. Future studies with a specific focus on the peripubertal stage are needed to clarify the role of the environment in shaping the neurobiological trajectories underlying TS.

ACKNOWLEDGMENTS This study was supported by the EU-FP7 framework project EMTICS under grant agreement n 278367.

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