Autism spectrum disorder and the cerebellum.

CHAPTER ONE

Autism Spectrum Disorder and the Cerebellum Esther B.E. Becker*,1, Catherine J. Stoodley†,1

*MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom † Department of Psychology, American University, Washington, District of Columbia, USA 1 Corresponding authors: e-mail address: [email protected]; [email protected]

Contents 1. Introduction 2. Cerebellar Organization 3. ASD Symptoms in Patients with Cerebellar Disorders 4. Motor Impairment in Autistic Individuals 5. Cerebellar Pathology in Autism 6. Cerebellar Differences in Autism: Structural Neuroimaging 7. Abnormal Cerebellar Activation in Autism 8. Autoimmune Studies in ASD Implicating the Cerebellum 9. Autism Genes in Mouse Cerebellar Development 10. Cerebellar Phenotypes in Rodent Models of Autism 11. Functional Evidence from Mouse Genetics 12. Conclusions Acknowledgment References

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Abstract The cerebellum has been long known for its importance in motor learning and coordination. Recently, anatomical, clinical, and neuroimaging studies strongly suggest that the cerebellum supports cognitive functions, including language and executive functions, as well as affective regulation. Furthermore, the cerebellum has emerged as one of the key brain regions affected in autism. Here, we discuss our current understanding of the role of the cerebellum in autism, including evidence from genetic, molecular, clinical, behavioral, and neuroimaging studies. Cerebellar findings in autism suggest developmental differences at multiple levels of neural structure and function, indicating that the cerebellum is an important player in the complex neural underpinnings of autism spectrum disorder, with behavioral implications beyond the motor domain.

International Review of Neurobiology, Volume 113 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-418700-9.00001-0

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2013 Elsevier Inc. All rights reserved.

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Esther B.E. Becker and Catherine J. Stoodley

1. INTRODUCTION Autism spectrum disorder (ASD) comprises a collection of neurodevelopmental diseases defined by deficits in communication and social interaction, and repetitive and restrictive behaviors (American Psychiatric Association, 2013). The etiology of autism is complex. The past decade has seen revolutionary advances in our understanding of the genetics of ASD and several hundreds of genetic variants have been identified (Berg & Geschwind, 2012; Betancur, 2011; Devlin & Scherer, 2012). In addition to its intricate genetic landscape, various environmental factors and specific gene–environment interactions are thought to contribute to the pathogenesis of ASD (Hallmayer et al., 2011; Herbert, 2010). Despite the recent advances in autism research, the molecular underpinnings and neural and circuit substrates of autism remain incompletely understood. ASD is widely regarded as a disorder of connectivity between different parts of the brain. A number of different brain areas have been implicated in autism (Amaral, Schumann, & Nordahl, 2008; Courchesne, Campbell, & Solso, 2011; Di Martino et al., 2013), including the cerebellum (Fatemi et al., 2012; Rogers, McKimm, et al., 2013). Termed the “little brain,” the cerebellum comprises 10% of total brain volume but contains more neurons than the rest of the brain and has the highest cell density of any brain area, approximately four times that of the neocortex (Herculano-Houzel, 2010). Its unique geometric arrangement, relatively simple structure, and sophisticated circuitry have been the subject of intense scrutiny for over two centuries. The cerebellum is at the crossroads between the sensory and motor systems and is essential for coordinating communications between these two systems. Importantly, the cerebellum is not necessary for basic elements of perception or movement, but rather controls the spatial accuracy and temporal coordination of movement. In addition, the cerebellum has long been implicated in motor skill learning. More recently, driven by increasingly sophisticated imaging techniques and advances in genetic studies, mounting evidence points to a role for the cerebellum in cognition and emotion. In this chapter, we will give a brief introduction to the cerebellum and discuss the different lines of evidence that link the cerebellum to autism.

Autism Spectrum Disorder and the Cerebellum

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2. CEREBELLAR ORGANIZATION The cerebellum lies behind the pons and is connected to the brain stem by three pairs of peduncles. Structurally, the cerebellum is composed of an outer mantle of gray matter (GM) (cerebellar cortex), which surrounds the internal white matter (WM), with three pairs of embedded deep nuclei (from medial to lateral, the fastigial, interposed, and dentate nuclei). Morphologically, the cerebellum is subdivided into a central vermis flanked by two hemispheres. The hemispheres are evolutionarily more recent and their volume increases progressively from lower vertebrates to higher mammals; this dramatic increase parallels the expansion of the neocortex in higher mammalian orders (Balsters et al., 2010). Notably, this region (cerebrocerebellum) receives input exclusively from the cerebral cortex. The cerebellum of higher vertebrates is highly folded into a series of parallel folia and subdivided into 3 lobes and 10 lobules (I–X). In humans, lobule VII is subdivided into Crus I, Crus II, and VIIB, and lobule VIII is divided into VIIIA and VIIIB (Fig. 1.1A).

Figure 1.1 Cerebellar anatomy. (A) Illustration of the lobes and lobules of the cerebellum, with the lobules color-coded (Spatially Unbiased Infratentorial (SUIT) Atlas; Diedrichsen et al., 2006, 2009). (B) Schematic representation of the basic cerebellar cell types and circuitry. The cerebellar neurons receive input from the climbing fibers (CF) originating in the inferior olive (IO) and the mossy fibers (MF) coming from the precerebellar nuclei (PCN). Purkinje cells (PC) form the sole output of the cerebellar cortex. Excitatory (þ) and inhibitory () inputs are indicated. BC, basket cell; DCN, deep cerebellar nuclei; GC, granule cell; GL, granular layer; GoC, Golgi cell; ML, molecular layer; PCL, Purkinje cell layer; PF, parallel fiber, SC, stellate cell; WM, white matter.

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Unlike the cerebral cortex, the cytoarchitecture of the cerebellar cortex is remarkably uniform. The cerebellar cortex has three layers and consists of five major cell types: the inhibitory stellate and basket cells, Golgi and Purkinje neurons, and the excitatory granule cells (GCs) (Fig. 1.1B). Each of the neuronal subtypes has a stereotypic and distinct morphology and discrete localization within the cerebellar cortex. Precise connections between the principal neurons are arranged in repeating circuit modules throughout the cerebellum. The cerebellum receives two types of excitatory inputs, mossy fibers originating from the precerebellar nuclei and climbing fibers coming from the inferior olive. The Purkinje cells (PCs) serve as the sole output of the cerebellar cortex. Their axons terminate on neurons in the cerebellar nuclei, which then project to other regions of the brain. The cerebellum is richly connected with the majority of the cerebral cortex, forming closed-loop cerebello-thalamo-cortico-pontine-cerebellar circuits. Different cerebellar functional regions can be broadly defined based on their patterns of connectivity with the cerebral cortex and the spinal cord, giving rise to a functional topography in the cerebellum (see Stoodley & Schmahmann, 2010 for review). The anterior lobe (lobules I–V) and lobule VIII are predominantly sensorimotor, with an upside-down representation of the body in the anterior lobe and secondary representations in lobule VIII. Lobules VI and VII (including Crus I, Crus II, and lobule VIIB) contribute to higher-level processes via connections with prefrontal and parietal cortices. The role of lobule IX is not yet clear, though it is important for the visual guidance of movement and may also be involved in the default network (see Buckner, Krienen, Castellanos, Diaz, & Yeo, 2011). Lobule X, the vestibulocerebellum, is connected with the vestibular nuclei. The posterior cerebellar vermis is thought to be involved in emotional modulation (Heath, 1977). In task-based imaging studies, activation patterns reflect the topographic arrangement of these different networks (Fig. 1.2) (Stoodley,

Figure 1.2 Cerebellar functional topography. Task-based functional MRI activation patterns reflect contralateral connections with cerebral cortex and ipsilateral connections with the spinal cord. Language tasks engage right-lateralized cerebellar lobule VII, spatial task activation is left-lateralized, and right-handed finger-tapping activates the right cerebellar anterior lobe and lobule VIII. Adapted and reproduced with permission from Stoodley and Schmahmann (2009).


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2012; Stoodley & Schmahmann, 2009). This provides a framework for interpreting cerebellar findings in ASD based on the localization of structural and functional differences to specific regions within the cerebellum.

3. ASD SYMPTOMS IN PATIENTS WITH CEREBELLAR DISORDERS Cerebellar disorders offer insight into the link between the cerebellum and ASD. While cerebellar damage can result in motor dysfunction, cerebellar lesions also cause the Cerebellar Cognitive Affective Syndrome (CCAS; Schmahmann & Sherman, 1998), a constellation of symptoms including impairments in language, spatial, and executive functions as well as affective dysregulation—symptoms that are relevant to ASD. Although the cerebellum is one of the first structures of the human brain to differentiate, it is not fully mature until the first postnatal years. This lengthy developmental phase makes the cerebellum particularly vulnerable to a broad spectrum of developmental disorders. Cerebellar malformations have been associated with a range of developmental impairments, including ASD symptomology (see review by Bolduc & Limperopoulos, 2009). Joubert syndrome (JS) is associated with hypoplasia of the cerebellar vermis, and 13–27% of JS children have clinically significant ASD symptoms (Ozonoff, Williams, Gale, & Miller, 1999). Smaller posterior vermal volume is also reported in Fragile X syndrome (FXS) and is associated with cognitive impairment (Mostofsky et al., 1998) and poorer social cognition (Cornish et al., 2005). Some patients with autism-associated 22q13.3 deletion (Phelan–McDermid) syndrome have severe hypoplasia of the vermis (Aldinger et al., 2013). Larger studies of cerebellar malformations also support a relationship between vermal malformations and positive ASD screens, whereas cerebellar hemisphere malformations are more often associated with selective deficits in executive function, language, or spatial cognition (Bolduc et al., 2011, 2012; Tavano et al., 2007). These findings reflect the connectivity patterns of these cerebellar regions, with the posterior vermis thought to connect to limbic structures and the posterolateral hemispheres forming cerebro-cerebellar loops with frontal and parietal association cortices (see Stoodley & Schmahmann, 2010 for review). In humans, rapid cerebellar growth takes place in the third trimester, which is impeded by preterm delivery. Preterm delivery leads to disruptions in the developmental program of the cerebellum, resulting in reduced thickness but increased packing density of GC layers and reduction in the density of Bergmann glia. Cerebellar injury associated with premature birth is

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followed by reduced prefrontal volume and an approximately 40-fold increase in ASD by age 2 (Limperopoulos, Chilingaryan, Guizard, Robertson, & Du Plessis, 2010). A significant relationship was found between vermal damage in preterm infants and a positive autism screen (Limperopoulos et al., 2007, 2008). Around 25% of patients with tuberous sclerosis complex (TSC) have cerebellar lesions (Eluvathingal et al., 2006; Vaughn et al., 2013), and reduction in cerebellar volume has been specifically associated with the TSC2 gene mutation (Weisenfeld et al., 2013). In TSC patients, autism severity is associated with a greater number of cerebellar tubers, and patients with cerebellar tubers have lower adaptive behavior, communication, and socialization scores (Eluvathingal et al., 2006; Weber, Egelhoff, McKellop, & Franz, 2000). In acquired cerebellar lesions due to tumor or stroke, affective disturbances were most often associated with vermal and paravermal lesions (see Schmahmann, Weilburg, & Sherman, 2007), whereas language difficulties are associated with right posterolateral hemisphere lesions (e.g., Riva & Giorgi, 2000; Stoodley, MacMore, Makris, Sherman, & Schmahmann, 2012).

4. MOTOR IMPAIRMENT IN AUTISTIC INDIVIDUALS Motor impairment and clumsiness has been noted since the earliest descriptions of ASD (Kanner and Asperger in Frith, 1991). Although only repetitive behaviors are included in the diagnostic criteria, motor impairment is a cardinal feature in ASD (Fournier, Hass, Naik, Lodha, & Cauraugh, 2010). Up to 80% of children with autism show motor coordination deficits and these are highly correlated with autistic severity and IQ (Green et al., 2009; Hilton, Zhang, Whilte, Klohr, & Constantino, 2012). Similarly, it has been suggested that dyspraxia is a core feature of ASD, rather than a comorbid or associated disorder (Dziuk et al., 2007; MacNeil & Mostofsky, 2012). Motor signs indicative of cerebellar dysfunction in ASD include eyemovement abnormalities, fine and gross motor deficits, impaired gait, balance and coordination, postural instability, and motor learning deficits (Table 1.1) (Freitag et al., 2007; Gowen & Hamilton, 2013; Jeste, 2011). ASD patients can be more variable in their motor performance, indicating difficulties maintaining performance consistency (e.g., Moran et al., 2013). Slower and more variable saccadic adaptation (Mosconi et al., 2013) could be related to structural differences in the posterior vermis in ASD. It has been

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Table 1.1 Cerebellar motor impairments in ASD Task Description Reference

Gross motor Scores on Movement- Freitag, Kleser, Schneider, and von Gontard (2007), Green et al. (2002), Landa skill ABC and PANESS, ball catching, hopping and Garrett-Mayer (2006), MacNeil and Mostofsky (2012), Moran, Foley, Parker, and Weiss (2013), Noterdaeme, Mildenberger, Minow, and Amorosa (2002), Whyatt and Craig (2012) Balance and Static balance, balance Chang, Wade, Stoffregen, Hsu, and Pan posture with sensory challenge, (2010), Esposito, Venuti, Apicella, and Muratori (2011), Fournier, Kimberg, et al. postural asymmetry (2010), Gepner and Mestre (2002), Greffou et al. (2012), MacNeil and Mostofsky (2012), Minshew, Sung, Jones, and Furman (2004), Molloy, Dietrich, and Bhattacharya (2003), Noterdaeme et al. (2002), Radonovich, Fournier, and Hass (2013), Travers et al. (2012) Gait

Variability in gait parameters

Hallett et al. (1993), Rinehart, Bellgrove, et al. (2006), Rinehart, Tonge, et al. (2006)

Praxis

Planning and performing skilled, coordinated movements

Dziuk et al. (2007), MacNeil and Mostofsky (2012)

Motor learning

Serial response time Mostofsky, Goldberg, Landa, and Denckla task, sequence learning (2000), Mostofsky et al. (2009), Muller, Kleinhans, Kemmotsu, Pierce, and Courchesne (2003)

Eyeblink Timing of conditioned Sears, Finn, and Steinmetz (1994), conditioning response Steinmetz, Tracy, and Green (2001) Mosconi et al. (2010, 2013), Takarae, Saccadic eye Saccadic and smooth Minshew, Luna, Krisky, and Sweeney movements, pursuit, rate and variability of adaptation (2004), Takarae, Minshew, Luna, and adaptation Sweeney (2004), Takarae, Minshew, Luna, and Sweeney (2007) Gesture and Motor imitation tasks Jones and Prior (1985), Rogers, Hepburn, Stackhouse, and Wehner (2003), Stieglitz imitation (facial expressions, gesture, using objects), Ham et al. (2011) lack of social gestures

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suggested that adults and adolescents with ASD are impaired in calibrating the relationship between their body and environment, and this is strongly correlated with their social and communication impairments (Linkenauger, Lerner, Ramenzoni, & Proffitt, 2012). Motor impairments are among the earliest signs of an autistic phenotype (Esposito et al., 2011; Teitelbaum, Teitelbaum, Nye, Fryman, & Maurer, 1998; Zwaigenbaum, Bryson, & Garon, 2013). Prospective studies of at-risk infants have shown that children who are later diagnosed with ASD show poorer fine and gross motor skills than typically developing (TD) and language-impaired children (Landa & Garrett-Mayer, 2006), and motor impairments are predictive of ASD outcome (Zwaigenbaum et al., 2013). Greater head lag during pull-to-sit was more frequently observed in infants at high-risk for ASD and was associated with ASD status upon follow-up (Flanagan, Landa, Bhat, & Bauman, 2012). Similarly, oral and manual motor skills in infancy and toddlerhood differentiated ASD individuals and predicted later speech fluency (Gernsbacher, Sauer, Geye, Schweigert, & Hill Goldsmith, 2008), and early motor delays are more common in infants at risk for ASD and are related to later communication delays (Bhat, Galloway, & Landa, 2012). Performance on motor tasks also correlates with ASD symptoms, including emotional/behavioral disturbance and communication disorder (Papadopoulos et al., 2012). ASD children that were significantly impaired during quiet stance had a higher number of restricted and repetitive behaviors (Radonovich et al., 2013). It has been suggested that the lack of gesture and imitation in ASD might be related to motor dysfunction, providing a mechanism by which cerebellar dysfunction could impact the core social communication symptoms of ASD (Gidley Larson & Mostofsky, 2006; Jones & Prior, 1985). Consistent with this, ASD children are impaired on both the recognition and imitation of gestures (Stieglitz Ham et al., 2011), and imitation impairment was associated with increased ASD symptoms and poorer joint attention (Rogers et al., 2003).

5. CEREBELLAR PATHOLOGY IN AUTISM Histopathological changes in the cerebellum have been observed in almost all postmortem brains of autistic individuals. The most consistent neuropathological finding in ASD is the loss of PCs (Allen, 2005; Bailey et al., 1998; Palmen, 2004). PC loss is widely distributed throughout the folia and observed in the vermis and particularly the cerebellar hemispheres


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(Allen, 2005; Bauman & Kemper, 2005; Whitney, Kemper, Bauman, Rosene, & Blatt, 2008). Because of the absence of glial hyperplasia in the cerebellum, it has been argued that loss of PCs likely occurs early on during cerebellar development (Allen, 2005; Bauman & Kemper, 2005). Also, widespread cellular dysplasia that has been observed in 62% of studied autistic brains suggests very early cerebellar developmental defects in ASD (Wegiel et al., 2010). In contrast, the preservation of basket and stellate cells in the presence of reduced PC numbers in some autistic brains suggests that PCs die after proper migration (Whitney, Kemper, Rosene, Bauman, & Blatt, 2009). In addition to cell loss, reduced packing density of PCs (Palmen, 2004) and reduced PC size (Fatemi et al., 2002) have been reported in autistic brains. Further observed cerebellar pathology in ASD includes a reduction of GCs and hypertrophy and atrophy of cerebellar nuclei (Allen, 2005; Bauman & Kemper, 2005; Kemper & Bauman, 1998). While these studies point to abnormal cerebellar pathology in ASD, some inconsistencies in the observations can be noted. These might be due to the heterogeneity in the ASD phenotype of the tested individuals. In the future, it will be important to carry out quantitative stereological studies in different regions of the cerebellum and at different ages in stratified patient populations. Some clues come from the genetically well-defined syndromic forms of ASD. Both postmortem and imaging studies from human patients with Rett syndrome (RTT) show cerebellar pathology, including progressive vermal hypoplasia, loss of PCs, and decreases in PC size (Bauman, Kemper, & Arin, 1995; Murakami, Courchesne, Haas, Press, & Yeung-Courchesne, 1992; Oldfors et al., 1990). PC loss and cerebellar glial abnormalities have also been reported in FXS (Greco et al., 2011; Sabaratnam, 2000). Similarly, TSC is associated with cerebellar atrophy and loss of PCs (Boer et al., 2008; Reith, Way, McKenna, Haines, & Gambello, 2011).

6. CEREBELLAR DIFFERENCES IN AUTISM: STRUCTURAL NEUROIMAGING Abnormalities in the cerebellum are among the most consistently reported brain differences in autism, and decreased bilateral cerebellar cortex was one of the most important markers for classifying adult ASD brains (Ecker et al., 2010). Cerebellar enlargement has been reported in autistic toddlers and young children (Courchesne et al., 2001). This early overgrowth is generally proportional to total brain volume (Stanfield et al.,

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2008) and likely related to cerebellar WM (Allen, 2005; Amaral et al., 2008; Courchesne, Webb, & Schumann, 2012). By adulthood, smaller cerebellar volume has been reported (Hallahan et al., 2009). Numerous imaging studies have reported cerebellar hypoplasia in autism, specifically smaller cerebellar vermal lobules VI and VII (e.g., Allen, 2005; Courchesne et al., 2011, 2012; Courchesne, Yeung-Courchesne, Hesselink, & Jernigan, 1988). Reduced vermal VI–VII is associated with ASD symptoms (Kaufmann et al., 2003), including reduced exploration and increased stereotyped and repetitive movements (Pierce & Courchesne, 2001). The imaging findings in other vermal lobules are inconsistent (e.g., Courchesne et al., 2012; Stanfield et al., 2008; Webb et al., 2009). Reduced size of the cerebellar hemispheres has also been observed and is correlated with vermal hypoplasia (Murakami, Courchesne, Press, Yeung-Courchesne, & Hesselink, 1989). Differences in the volume of the vermis and anterior lobe and abnormal left-lateralization in lobule VIIIA have been associated with language impairment in ASD (Hodge et al., 2010). Differences in cerebellar WM tracts have also been reported. Increased diffusivity of the superior cerebellar peduncles suggests abnormal connectivity between the cerebellum and its rostral connections (Sivaswamy et al., 2010), and Catani et al. (2008) found a correlation between the degree of social impairment and the integrity of the superior cerebellar peduncle. In ASD children, cerebellar WM abnormalities were associated with repetitive behaviors (Cheung et al., 2009). Voxel-based morphometry studies have reported both increases and decreases in cerebellar GM and WM (Fig. 1.3). Decreased GM is consistently found in midline IX, right Crus I, and lobule VIII in ASD, and in some studies lobule IX was the most significant cluster in the entire brain; increased GM was reported in lobule VI (Cauda et al., 2011; Duerden, Mak-Fan, Taylor, & Roberts, 2012; Nickl-Jockschat et al., 2012; Yu, Cheung, Chua, & McAlonan, 2011). Resting-state activity in lobule IX and right Crus I most strongly correlates with the default mode network (Buckner et al., 2011), and healthy males engage Crus I bilaterally during both theory of mind and empathy tasks (Vollm et al., 2006). In ASD children, GM reductions bilaterally in Crus II and in vermal lobules VIII–IX correlated with communication scores (Riva et al., 2013), and lower GM in Crus I was associated with increased repetitive and stereotyped behaviors (Rojas et al., 2006). Although increases in right Crus I have been reported, these were in a different region of right Crus I that is thought to be part of


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Figure 1.3 Activation likelihood estimate (ALE) meta-analysis revealing GM differences in ASD. Structural GM increases in VI/Crus I are shown in red-orange and decreases in Crus I and IX are shown in blue-green. Adapted and reproduced with permission from Cauda et al. (2011).

fronto-parietal cognitive control networks (Buckner et al., 2011). GM increases in lobule VI correlated with poorer social and communication scores (Rojas et al., 2006). These findings suggest that the structural differences within the cerebellum are related to different aspects of the core ASD deficits.

7. ABNORMAL CEREBELLAR ACTIVATION IN AUTISM Functional imaging has revealed task-dependent differences in cerebellar activation in ASD in a wide range of tasks. Allen and Courchesne (2003) found greater and more widespread cerebellar activation during a simple motor task, but less attention-related activation in the cerebellum in ASD individuals. Reduction in cerebellar activity in ASD is often accompanied by an increase in activation in cortical regions, particularly prefrontal regions (e.g., Mostofsky et al., 2009; Takarae et al., 2007). This may reflect compensatory activity and suggests that cerebellar dysfunction taxes topdown systems. In the resting state, ASD children showed decreased regional homogeneity in bilateral Crus I, and greater regional homogeneity

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bilaterally in lobule VIII (Paakki et al., 2010). Based on resting-state studies of cerebro-cerebellar networks (e.g., Buckner et al., 2011), differences in Crus I could reflect alterations in default or prefrontal–parietal control network activity, whereas changes in lobule VIII could be related to repetitive or stereotyped behaviors. During more complex motor tasks, ASD participants showed reduced anterior cerebellar activation during sequential finger-movement tasks (e.g., Gilbert, Bird, Brindley, Frith, & Burgess, 2008; Muller et al., 2003; Villalobos, Mizuno, Dahl, Kemmotsu, & Muller, 2005), and less activation bilaterally in Crus I during visually guided saccades and in VI/Crus I during visual pursuit (Takarae et al., 2007). During visual–spatial attention, both ASD and unaffected siblings showed atypical engagement of frontal– cerebellar circuits, which correlated with ASD traits in autistic participants and their siblings (Belmonte, Gomot, & Baron-Cohen, 2010). ASD participants did not engage the posterior vermis during spatial attention, where structural differences in ASD are widely reported (Haist, Adamo, Westerfield, Courchesne, & Townsend, 2005). During eye movements, the typically-developing (TD) group activated the oculomotor vermis, whereas the ASD group activated Crus I (Haist et al., 2005), suggesting that the ASD group was not using typical eye-movement regions of the cerebellum but instead utilized association cerebro-cerebellar loops. While not all studies find cerebellar differences during face processing (e.g., Corbett et al., 2009; Schulte-Ruther et al., 2011), others report differences particularly during direct gaze processing (Pitskel et al., 2011). During explicit and implicit processing of facial expressions, ASD adults showed greater activation in the anterior vermis during implicit processing, whereas TD adults showed greater activation in this region during explicit processing (Critchley et al., 2000). These data suggest that the groups engage different cerebro-cerebellar circuits when processing facial expressions. As in structural imaging, functional imaging also supports lobule VII dysfunction in ASD. During emotional processing, ASD groups showed reduced activity in lobule VII (Crus I, Crus II) during processing of music (Caria, Venuti, & de Falco, 2011), facial and vocal stimuli (Wang, Lee, Sigman, & Dapretto, 2007), and emotional images (Silani et al., 2008). Reduced activation in right VII has also been reported during language tasks, including semantic processing (Harris et al., 2006; Knaus, Silver, Lindgren, Hadjikhani, & Tager-Flusberg, 2008; Tesink et al., 2011) and anomalous sentence processing (Groen et al., 2010). Significant correlations were found in the ASD group between the N-acetyl-aspartate concentration


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in the right cerebellar hemisphere and verbal fluency scores (Kleinhans, Schweinsburg, Cohen, Muller, & Courchesne, 2007), though no significant differences in cerebellar activation were reported during prosodic speech (Hesling et al., 2010) or word categorization (Gaffrey et al., 2007). Reduced activation in right Crus I and II (together with frontal and parietal cortices) has also been reported during executive function paradigms (Solomon et al., 2009), though differences are not always found in ASD participants during executive function tasks. For attention tasks, change detection and attention shifting tasks have shown both greater (right I–IV; Gomot et al., 2006) and reduced (lobule V; Shafritz, Dichter, Baranek, & Belger, 2008) activation in the anterior cerebellum. In summary, cerebellar functional activation differences have been found in both resting-state and task-based neuroimaging studies. The tasks in which cerebellar differences are reported go beyond motor tasks and include language and executive function measures, and in many cases correspond with regions in which cerebellar structural differences have been identified in ASD.

8. AUTOIMMUNE STUDIES IN ASD IMPLICATING THE CEREBELLUM Autoimmune mechanisms are considered to be one of the environmental factors contributing to autism (Braunschweig & Van de Water, 2012). Maternal brain-reactive antibodies are thought to access the fetal brain during pregnancy as the fetal blood–brain barrier is not yet fully formed. Indeed, studies have identified the presence of antibodies that bind to human fetal brain tissue in a subset of women who have children with autism (Braunschweig et al., 2008; Croen et al., 2008; Singer et al., 2008; Zimmerman et al., 2007). Several studies have described antibodies that are reactive to cerebellar proteins in ASD (Dalton et al., 2003; Goines et al., 2011; Wills et al., 2009). Dalton et al. (2003) described maternal antibodies from a mother of children with autism and language disorder binding to cerebellar PCs. When the maternal serum was injected into pregnant mice during gestation, the offspring exhibited altered exploration and motor coordination and changes in cerebellar magnetic resonance spectroscopy. Moreover, in humans the presence of antibodies against cerebellar proteins is associated with a worsening of cognitive function and aberrant behaviors including deficits in communication (Braunschweig et al., 2012; Goines et al., 2011). Together, these studies suggest that maternal antibodies to

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cerebellar proteins might be a cause of ASD. However, it is unclear which cerebellar proteins are targeted by these auto-antibodies and what the underlying molecular mechanisms might be. It is important to identify the cerebellar target antigens as this might give important insights into the pathogenesis of ASD in general and might also lead to the identification of important biomarkers to ascertain autism risk. Furthermore, these studies might also give important insight into the molecular basis of gene– environment interactions in autism. For example, the presence of a single nucleotide polymorphism in the promoter of the human MET gene, encoding Met proto-oncogene receptor tyrosine kinase, is highly correlated with the presence of maternal antibodies, potentially by dysregulating maternal cytokine production and hence immune function (Heuer, Braunschweig, Ashwood, Van de Water, & Campbell, 2011).

9. AUTISM GENES IN MOUSE CEREBELLAR DEVELOPMENT Much of our current understanding of the cellular and molecular mechanisms governing the formation of the cerebellum has come from the analysis of mutant mice with cerebellar phenotypes. A number of autism candidate genes are known to have important functions in cerebellar development. However, most of the cerebellar mouse mutants were generated before the respective genes were associated with autism. Consequently, in most of these mutants, autism-related behaviors have not yet been rigorously assessed. Several studies have found a genetic association between the gene encoding the transcription factor engrailed homeobox 2 (EN2) and autism (see curated databases SFARI Gene and Autism KB; Basu, Kollu, & Banerjee-Basu, 2009; Xu et al., 2012). In mice, En2 contributes to the early specification of all cerebellar neurons and is required for late embryonic morphogenesis through its inhibition of migration, growth, and differentiation. Mice deficient for En2 display abnormal cerebellar foliation, hypoplasia, and a reduction in cerebellar neuron numbers (Kuemerle, Zanjani, Joyner, & Herrup, 1997; Millen, Wurst, Herrup, & Joyner, 1994). Consistent with aberrant cerebellar development, these mice display a motor phenotype including abnormal motor coordination and grip strength (Cheh et al., 2006). En2 knockout mice also exhibit other behavioral impairments that are relevant to autism, including social deficits and increased grooming (Brielmaier et al., 2012; Cheh et al., 2006). However,


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it is unclear whether the latter result specifically from loss of En2 in the cerebellum, as En2 is also expressed, albeit at lower levels, in other parts of the brain, including the cortex and the thalamus (Brielmaier et al., 2012). RAR-related orphan receptor alpha (ROR-alpha) is another transcription factor crucial for cerebellar development that recently has been associated with autism (SFARI Gene). It has long been known that ROR-alpha is vital for early PC development (Boukhtouche et al., 2006; Gold, Gent, & Hamilton, 2007). Both the staggerer mouse, harboring a spontaneous intragenic Rora deletion, and targeted Rora knockout mice display abnormal PC development, followed by progressive loss of PCs and secondary loss of GCs (Sidman, Lane, & Dickie, 1962) (see also Mouse Genome Database (MGD); Eppig et al., 2012). Behaviorally, Rora-deficient mice are ataxic and exhibit impaired motor coordination and learning phenotypes (MGD). PC development is also known to be under control of the transcription factor forkhead box 2 (Foxp2). Human mutations in FOXP2 cause developmental speech and language deficits and are associated with autism (SFARI Gene, Autism KB). Mice deficient for the Foxp2 gene show impairments in PC development, cerebellar radial glia morphology, and GC migration (Shu, 2005). Furthermore, mice with a language disorderimplicated missense mutation (R522H) in Foxp2 also show cerebellar hypoplasia, abnormal PC development, cerebellar synaptic deficits, and impaired motor learning (Fujita et al., 2008; Groszer et al., 2008). The extracellular matrix protein reelin is important for neuronal migration in both the cortex and the cerebellum (Rice & Curran, 2001). Several studies have found a genetic association between the RELN gene and autism, and rare mutations in RELN have been identified in individuals with ASD (SFARI Gene). Furthermore, reelin signaling was impaired in the frontal cortex and cerebellum of autistic postmortem brains (Fatemi et al., 2005). In the cerebellum, reelin is highly expressed in GCs. Reln mouse mutants, including the classic spontaneous reeler mouse, display cerebellar hypoplasia with severely reduced GC numbers and secondary PC migration deficits (Mariani, Crepel, Mikoshiba, Changeux, & Sotelo, 1977) (MGD). Behaviorally, Reln mouse mutants display ataxia, motor coordination, and balance deficits (MGD). Consistent with the findings in mice, human RELN mutations have also been associated with profound cerebellar hypoplasia (Hong et al., 2000). The adaptor proteins Dab1 and CrkL are downstream effectors in the reelin-signaling pathway (Ballif et al., 2004; Park & Curran, 2008). Similar to the reeler mice, mice deficient for Dab1 (scrambler mouse mutant) or Crkl knockout mice display cerebellar hypofoliation and failure

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of PC migration and dendritic differentiation (Park & Curran, 2008; Sweet, Bronson, Johnson, Cook, & Davisson, 1996). Both human genes DAB1 and CRKL are associated with ASD (Autism KB). Interestingly, Crkl is implicated in Met signaling (Furge, Zhang, & Van de Woude, 2000), and the human MET gene is strongly associated with autism (SFARI Gene, Autism KB) (for more information, see Chapter 5). In the cerebellum, Met is expressed postnatally in proliferating GC precursors and adult GCs and required for normal cerebellar development (Honda et al., 1995; Ieraci, Forni, & Ponzetto, 2002). Mice harboring a hypomorphic Met receptor display cerebellar hypoplasia with foliation defects and reduced GC proliferation (Ieraci et al., 2002). Consistently, these mice display impaired motor coordination. Another autism-implicated signaling molecule involved in cerebellar development is phosphatase and tensin homolog (PTEN). Rare single gene variants in human PTEN have been associated with ASD including Cowden syndrome (SFARI Gene). Mice deficient in Pten are ataxic and display aberrant neuronal proliferation and migration deficits in the cerebellum (Backman et al., 2001; Kwon et al., 2001; Marino et al., 2002). Ca2þ-dependent activator protein for secretion 2 (CADPS2) is a vesicular protein highly expressed in the parallel fiber terminals of cerebellar GCs and involved in the secretion of the neurotrophic factors NT-3 and BDNF (Sadakata, 2004; Speidel et al., 2003), both of which are essential for cerebellar development. Rare variants in human CADPS2 are associated with autism (Cisternas, Vincent, Scherer, & Ray, 2003) and there is also expression, linkage, and copy number variant (CNV) evidence for CADPS2 in autism (Autism KB). Mice deficient in Cadps2 exhibit cerebellar foliation defects, impaired PC differentiation, and GC migration abnormalities (Sadakata, Kakegawa, et al., 2007). Cadps2-deficient mice also show behavioral deficits related to aberrant cerebellar function including impaired motor coordination and eye movements (Sadakata, Kakegawa, et al., 2007). Moreover, these mice display cognitive deficits including impaired spatial memory, social behavior, and circadian rhythm (Sadakata, Washida, et al., 2007). However, it remains unclear whether the latter are due to cerebellar deficits or altered circuit activity elsewhere in the brain. Lastly, mouse mutants deficient in the Gabrb3 gene encoding the gamma-aminobutyric acid (GABA) A receptor, subunit beta 3, have revealed a role for this receptor in cerebellar development. GABRB3 maps to chromosomal region 15q11–q13, the most common known cytogenetic abnormality in individuals with ASD (Devlin & Scherer, 2012).


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Furthermore, rare variants in the human GABRB3 have been associated with autism (SFARI Gene, Autism KB). Gabrb3 protein expression was found to be reduced in autism postmortem cerebellum (Fatemi, Reutiman, Folsom, & Thuras, 2008). Gabrb3-deficient mice have a variety of neurological phenotypes including impaired motor coordination (DeLorey et al., 1998). Neuropathologically, Gabrb3-deficient mice display cerebellar hypoplasia, particularly of lobules II–VII (DeLorey, Sahbaie, Hashemi, Homanics, & Clark, 2008). These mice also show impairments in social and exploratory behavior (DeLorey et al., 2008). However, it should be noted that Gabrb3 is expressed widely in the developing nervous system including the cortex, hippocampus, and thalamus (Laurie, Wisden, & Seeburg, 1992).

10. CEREBELLAR PHENOTYPES IN RODENT MODELS OF AUTISM Over the past several years, an increasing number of rodent models of autism have been developed and characterized in terms of their molecular, cellular, and behavioral phenotypes and responses to drug treatment. The models that have been assessed for cerebellar phenotypes will be discussed here. One of the earliest autism rodent models is the valproic acid (VPA) rat model (Rodier, 1996). Injection of pregnant dams with VPA causes autism-related behavior in their offspring including impaired social behavior, exploratory activity, and repetitive/stereotypic-like hyperactivity (Roullet, Wollaston, deCatanzaro, & Foster, 2010; Schneider & Przewłocki, 2004; Yochum, Dowling, Reuhl, Wagner, & Ming, 2008). Motor performance has not been well assessed in these models, although delayed motor maturation and impairments in fine motor skills have been reported (Reynolds, Millette, & Devine, 2012; Wagner, Reuhl, Cheh, McRae, & Halladay, 2006). VPA-exposed offspring show a number of prominent cerebellar anomalies including cerebellar hypoplasia, a reduction of PCs, reduced PC spine density, and increased apoptosis of cerebellar GCs (Ingram, Peckham, Tisdale, & Rodier, 2000; Mychasiuk, Richards, Nakahashi, Kolb, & Gibb, 2012; Yochum et al., 2008). Cerebellar phenotypes including aberrant neuropathology, electrophysiology, and behavior have also been demonstrated in several well-established genetic mouse models of autism. The transcriptional regulator methylCpG-binding protein 2 (MeCP2), which is mutated in RTT, shows

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dramatic developmental increases in expression in the cerebellum during the period of extensive synapse formation (Mullaney, Johnston, & Blue, 2004). Mecp2-deficient mice exhibit RTT-like phenotypes including motor impairments (Chen, Akbarian, Tudor, & Jaenisch, 2001; Guy, Hendrich, Holmes, Martin, & Bird, 2001). Motor coordination and learning are also impaired in MeCP2 knockin mice that harbor the RTT-associated mutation T158A (Goffin et al., 2011). Consistent with the observed motor deficits, cerebellar pathology is observed in the mutant mice. Cerebellar volume is significantly reduced in Mecp2-deficient mice (Belichenko, Belichenko, Li, Mobley, & Francke, 2008), and the cell bodies of cerebellar GCs are smaller and more densely packed (Chen et al., 2001). Given these phenotypes, a number of expression studies have been carried out in the RTT mice to identify the underlying molecular deficits in the cerebellum. Hundreds of genes were found to be significantly changed in the cerebella of both MecP2deficient and -overexpression mice (Ben-Shachar, Chahrour, Thaller, Shaw, & Zoghbi, 2009). Interestingly, MeCP2 was shown to directly regulate the expression of reelin in mouse cerebellum (Jordan, Li, Kwan, & Francke, 2007), hinting at a potential common molecular pathway underlying cerebellar deficits in ASD. Similarly, FXS model mice deficient in Fmr1 display cerebellar pathology and aberrant cerebellar function. A mouse MRI study on Fmr1-deficient mice revealed anatomical changes only in the cerebellum including decreased volume and neuronal loss in the deep cerebellar nuclei (Ellegood, Pacey, Hampson, Lerch, & Henkelman, 2010). Moreover, Fmr1-deficient mice exhibit abnormal PC morphology with longer dendritic spines (Koekkoek et al., 2005). Behaviorally, these mice are impaired in eyeblink conditioning, a cerebellum-dependent form of associative learning, similar to FXS and ASD patients (Koekkoek et al., 2005; Tobia & Woodruff-Pak, 2009). Standard motor function is only mildly impaired in the Fmr1-deficient mice, but they show significant cerebellum-dependent oromotor defects that might be related to articulation deficits in humans with FXS (Roy et al., 2011). Recently, abnormalities in the cerebellar–prefrontal circuitry were reported in Fmr1 knockout mice, resulting in abnormal dopamine transmission in the prefrontal cortex (Rogers, Dickson, et al., 2013). Mice with maternal deficiency (m/pþ) for the Ube3a gene have been generated as a model system for Angelman syndrome ( Jiang et al., 1998; Miura et al., 2002). When maternally inherited, Ube3a is strongly expressed in PCs and cerebellar neurons in the molecular and granular layers and in


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some cortical and hippocampal neurons (Albrecht et al., 1997; Dindot, Antalffy, Bhattacharjee, & Beaudet, 2008). Ube3am/pþ mice display several cerebellar phenotypes including abnormal gait and impaired motor coordination and balance (Heck, Zhao, Roy, LeDoux, & Reiter, 2008; Jiang et al., 1998; Miura et al., 2002). Similar to the Fmr1 knockout mice, Ube3am/pþ mice also display cerebellar-dependent deficits in oromotor function (Heck et al., 2008). Furthermore, Ube3am/pþ mice exhibit fast oscillations sustained by abnormally increased PC firing rate and rhythmicity and also abnormal PC spine morphology (Cheron, Servais, Wagstaff, & Dan, 2005; Dindot et al., 2008). Recently, it was found that motor dysfunction in Ube3am/pþ mice is caused by decreased tonic inhibition in cerebellar GCs due to reduced degradation of the GABA transporter 1 (Egawa et al., 2012). Interestingly, the motor deficits in the Ube3am/pþ mice could be alleviated by administration of the selective extrasynaptic GABAA receptor agonist THIP (Egawa et al., 2012). It will be important to establish whether the Ube3am/pþ mice also exhibit autism-like phenotypes including social and communication deficits and restricted behaviors and whether these phenotypes can be rescued with THIP. Nonsyndromic forms of autism are often associated with mutations in cell adhesion molecules including SHANKS and neuroligins (Betancur, Sakurai, & Buxbaum, 2009; Peça & Feng, 2012). SHANK3 is highly expressed in the molecular and granular layer of the cerebellum (Bo¨ckers et al., 2001; Peça et al., 2011). Recently, several mutant Shank3 mouse models have been generated and shown to recapitulate autistic behaviors relevant to individuals with SHANK3 mutations (Jiang & Ehlers, 2013). While a possible cerebellar pathology has not been analyzed yet in these mouse mutants, motor coordination defects have been described in two Shank3knockout lines (Bozdagi et al., 2010; Yang et al., 2011). Mutant Neuroligin-3 (Nlgn3) mice, either harboring an ASD-associated point mutation (R451C) or deficient in Nlgn3, display autism-related behaviors such as impaired social interaction and communication (Radyushkin et al., 2009; Tabuchi et al., 2007). Nlgn3-deficient mice also exhibit cerebellar-dependent motor incoordination (Baudouin et al., 2012). Furthermore, these mice show disrupted cerebellar heterosynaptic competition and deficits in cerebellar metabotropic glutamate receptordependent synaptic plasticity, similar to those observed in Fmr1-deficicient mice, suggestive of a shared cerebellar pathophysiology in these mouse models (Baudouin et al., 2012; Koekkoek et al., 2005).

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11. FUNCTIONAL EVIDENCE FROM MOUSE GENETICS While there is mounting evidence for cerebellar phenotypes in mouse mutants for autism genes as discussed above, it remains controversial whether these are a bystander effect or are key to the disease pathogenesis. Using conditional mouse knockouts for TSC proteins, recent studies have provided functional evidence that abnormal PC function is an important contributor to autism-related behavior in the mouse. TSC is an autosomal-dominant disorder with high rates of comorbid ASD caused by mutations in either TSC1 or TSC2. As discussed above, the cerebellum has been implicated in TSC, and cerebellar pathology is correlated with the severity of ASD symptoms in TSC patients (Eluvathingal et al., 2006; Weber et al., 2000). Tsc1 and Tsc2 are strongly expressed in the mouse cerebellum (Gutmann et al., 2000). To investigate the contribution of cerebellar TSC1 to autistic-like behavior in a mouse model, Tsai et al. (2012) created conditional mouse mutants with Tsc1 deleted only in PCs (Tsc1PC). PC-specific loss of Tsc1 results not only in progressive ataxia but also causes autistic-like behaviors including impaired social interaction, repetitive behavior, and abnormal ultrasonic vocalizations. Interestingly, the Tsc1PC heterozygote mice, which more accurately mimic the human genetic condition, display no motor impairments but similar social deficits compared to the homozygous Tsc1PC knockout mice, suggesting that motor deficits are not responsible for the abnormal social behavior. On a cellular level, Tsc1deficient PCs exhibit abnormal spine density and reduced excitability. Furthermore, progressive loss of PCs occurs in the homozygous mice, likely causing the observed motor impairments. It will be important to determine whether cerebellar output from the cerebellar nuclei is reduced and also which connections to other brain structures are affected in the Tsc1PCdeficient mice. This will give important insights into the cerebello-cortical circuitry underlying the observed autism-related behaviors. Similar findings were observed upon deletion of Tsc2, specifically in PCs. Homo- and heterozygous Tsc2PC mutant mice display PC degeneration and motor impairment (Reith et al., 2011). Furthermore, heterozygous Tsc2PCdeficent mice show autistic-like behavior including increased repetitive behavior and social deficits (Reith et al., 2013). TSC1 and TSC2 are known to negatively regulate the mammalian target of rapamycin (mTOR) signaling. Importantly, the pathological and behavioral deficits in the Tsc1PC- and Tsc2PC-deficient mice are prevented upon


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treatment of the mice with the mTOR inhibitor rapamycin (Reith et al., 2011, 2013; Tsai et al., 2012), identifying the mTOR signaling pathway as a key molecular mechanism in the cerebellum contributing to autistic-like behavior.

12. CONCLUSIONS There is ample evidence at multiple levels of inquiry that link differences in cerebellar structure and function to autism. From mouse models of autism-related genes to human studies of cerebellar malformations, cerebellar dysfunction is related to the core behaviors that comprise the autism spectrum. Vice versa, differences in cerebellar structure and function, and behavioral evidence of cerebellar-type motor impairments, have been clearly documented in autistic populations. Given the evidence presented here, it seems unlikely that changes in cerebellar structure and function in autism are a mere anatomical beacon of dysfunction elsewhere (Ziats & Rennert, 2013). Instead, the cerebellum appears to be part of extensive neural networks that together govern the social, communication, and repetitive/restrictive behaviors impaired in autism. Future research will undoubtedly extend our current understanding of the link between the cerebellum and autism. It will be important to further characterize the lobular localization of cellular, molecular, and structural differences in the cerebellum, their relevance to specific motor and nonmotor autistic symptoms, and the effects of these differences on downstream cortical targets. As extensive exome and whole genome sequencing studies of autistic patients are now underway, these discoveries should be linked to specific human gene mutations. This will give important insight into the specific molecular and neural pathways that underlie distinct autistic traits. The generation of temporally and spatially conditional mouse models will help to clarify which cell types and autism symptoms are affected by specific human genetic mutations. Ultimately, our increasing knowledge of the specific role of the cerebellum in ASD should lead to better diagnosis and promising targets for more effective clinical interventions.

ACKNOWLEDGMENT E. B. is a Royal Society Research Fellow. We thank Friederike Winter for critical reading of the chapter.

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