Autistic-like behavior and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice
By Peter T. Tsai, Court Hull, Yunxiang Chu, Emily Greene-Colozzi, Abbey R. Sadowski, J. M. Leech, Jason Steinberg, J. Crawley, Wade G. Regehr, Mustafa Sahin. Nature, 2012
834 citations recorded by the source corpus.
Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.
Subfields: Immunology, Oncology, Physiology
View Paper: https://www.semanticscholar.org/paper/1ce9f5a5e25352fc54b8055ed41b9691e01d8abe
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Citations in the corpus
- Disentangling the heterogeneity of autism spectrum disorder through genetic findings (2014, positive): “32 These phenotypes provide the first strong evidence that pure cerebellar dysfunction can have a profound impact on social behaviour.”
- The Cerebellum, Sensitive Periods, and Autism (2014, background): “Purkinje cell-specific knockout of the tuberous sclerosis gene TSC1 leads to autism-like deficits, including deficient social interaction with other mice, increased repetitive self-grooming, diminished mother-pup interaction, and perseveration when the rule is switched on a T-maze (Tsai et al., 2012”
- Purkinje cells directly inhibit granule cells in specialized regions of the cerebellar cortex (2016, neutral): “Cerebellar dysfunction results in ataxia and dystonia, and more recently has been implicated in autism spectrum disorder (Fatemi et al., 2012; Tsai et al., 2012; Wang et al., 2014).”
- Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits (2014, neutral): “Mean ± SD. (I) Correlation between p-mTOR and PSD95 (R2 = 0.598, p 0.001).”