Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

Cupolillo, Dario; Hoxha, Eriola; Faralli, Alessio; Luca, Annarita De; Rossi, Ferdinando; Tempia, Filippo; Carulli, Daniela

doi:10.1038/npp.2015.339

Cited by 137 publications

(117 citation statements)

References 46 publications

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“…Previous studies in mouse models have shown that cerebellar dysfunction is sufficient to generate autism-related behaviors in mice 7,23,33,34 but have not examined the specific cerebellar regions responsible for these functions. While differences in RCrusI are strongly associated with ASD, the contribution of RCrusI dysfunction to ASD remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice

et al. 2017

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Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here, neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI–inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted.

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Section: Discussionmentioning

confidence: 99%

Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice

et al. 2017

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“…PTEN was first identified as a tumor suppressor (Li et al, 1997) but later also found to be associated with neurodevelopmental conditions such as epilepsy, macrocephaly, and autism (Goffin et al, 2001; Butler et al, 2005; Buxbaum et al, 2007; Orrico et al, 2009; Varga et al, 2009; McBride et al, 2010; Redfern et al, 2010; Stein et al, 2010; Schaaf et al, 2011; O’Roak et al, 2012b; Busa et al, 2013; De Rubeis et al, 2014; Hobert et al, 2014; Marchese et al, 2014; Vanderver et al, 2014; Codina-Sola et al, 2015; D’Gama et al, 2015; Johnston and Raines, 2015; Krumm et al, 2015; Spinelli et al, 2015; Tammimies et al, 2015; Cupolillo et al, 2016; Schwerd et al, 2016; Tilot et al, 2016). PTEN expression in the brain is positively correlated with the developmental stages of neuronal dendrite formation and synaptogenesis suggesting a role in regulating neuronal function (Perandones et al, 2004).…”

Section: Signaling Molecules Actively Regulate Dendritic Spine and Dementioning

confidence: 99%

“…Knockdown of PTEN in basaolateral amygdala and dentate gyrus, however, does not affect spine density, but spine morphology is dramatically altered with an increase of mature mushroom-shaped spines (Haws et al, 2014). The Pten knockout in cerebellum also results in significant alterations in neuronal morphology of Purkinje cells including swelling of dendrites, and an increase of axonal bouton and dendritic spine size (Cupolillo et al, 2016). The impact of PTEN on spine stability is dependent on the phosphorylation status of its serine/threonin residues and the PDZ-binding motif in its C-terminus (Zhang et al, 2012).…”

Section: Signaling Molecules Actively Regulate Dendritic Spine and Dementioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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“…Our behavioral data on autistic-like behaviors in mice with predominant expression of mutant DISC1 in PCs are consistent with those reported for various genetic and environmental models focused on cerebellar pathology and dysfunction, including the maternal immune activation mouse model (Shi et al, 2009; Xu et al, 2013), an early postnatal hypothyroidism rat model (Akaike et al, 1991; Sadamatsu et al, 2006), Staggerer mice (Doulazmi et al, 2001; Goldowitz and Koch, 1986; Herrup and Mullen, 1979; Herrup et al, 1996; Lalonde et al, 1996; Misslin et al, 1986), Shank2 and 3 knockout (KO) mice (Beri et al, 2007; Jiang and Ehlers, 2013; Peca et al, 2011; Peter et al, 2016), Enlarged2 KO mice (Brielmaier et al, 2012; Cheh et al, 2006; Kuemerle et al, 2007; Kuemerle et al, 1997; Millen et al, 1994), Fmr1 KO mice (Ellegood et al, 2010; Koekkoek et al, 2005; Olmos-Serrano et al, 2011; Yuskaitis et al, 2010), and PTEN conditional KO mice (Cupolillo et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice

Shevëlkin

Terrillion

Abazyan

et al. 2017

Neurobiology of Disease

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In addition to motor function, the cerebellum has been implicated in cognitive and social behaviors. Various structural and functional abnormalities of Purkinje cells (PCs) have been observed in schizophrenia and autism. As PCs express the gene Disrupted-In-Schizophrenia-1 (DISC1), and DISC1 variants have been associated with neurodevelopmental disorders, we evaluated the role of DISC1 in cerebellar physiology and associated behaviors using a mouse model of inducible and selective expression of a dominant-negative, C-terminus truncated human DISC1 (mutant DISC1) in PCs. Mutant DISC1 male mice demonstrated impaired social and novel placement recognition. No group differences were found in novelty-induced hyperactivity, elevated plus maze test, spontaneous alternation, spatial recognition in Y maze, sociability or accelerated rotarod. Expression of mutant DISC1 was associated with a decreased number of large somata PCs (volume: 3000–5000 μm3) and an increased number of smaller somata PCs (volume: 750–1000 μm3) without affecting the total number of PCs or the volume of the cerebellum. Compared to control mice, attached loose patch recordings of PCs in mutant DISC1 mice revealed increased spontaneous firing of PCs; and whole cell recordings showed increased amplitude and frequency of mEPSCs without significant changes in either Rinput or parallel fiber EPSC paired-pulse ratio. Our findings indicate that mutant DISC1 alters the physiology of PCs, possibly leading to abnormal recognition memory in mice.

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Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

Cited by 137 publications

References 46 publications

Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice

Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice

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