Journal Article

Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice

Greene-Colozzi, Emily, Regehr, Wade G., Chu, YunXiang, Steinberg, Jason, Hull, Court, Leech, Jarrett M., Sadowski, Abbey R., Tsai, Peter T., Crawley, Jacqueline N., Sahin, Mustafa

2012

Overview

Both heterozygous loss and homozygous loss of Tsc1 in mouse cerebellar Purkinje cells (PCs) result in autistic-like behaviours, which can be prevented by treatment with the mTOR inhibitor, rapamycin; these findings demonstrate critical roles for PCs in autistic-like behaviours in mice. A novel mouse autism model Tuberous sclerosis is a rare tumour-causing genetic disorder that results from mutation of the genes TSC1 or TSC2 . Affected individuals often also have autism spectrum disorder associated with cerebellar pathology. Because clinical studies have implicated cerebellar dysfunction in the pathogenesis of autism, Mustafa Sahin and colleagues studied the functional consequences of disrupting the cerebellar Tsc1 gene in mice. The mutant mice exhibit pathological features common in patients with autism —reduced Purkinje cell numbers and increased markers of neuronal stress — and mice lacking Tsc1 in cerebellar Purkinje cells display autism-related behaviours. Both the cerebellar pathology and behavioural features are ameliorated by treating the mice with the mTOR inhibitor rapamycin. Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders 1 , 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 2 , 3 , and isolated cerebellar injury has been associated with a higher incidence of ASDs 4 . 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 5 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 6 and correlate cerebellar pathology with increased ASD symptomatology 7 , 8 . Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs 9 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1689/1373 / 631/378/340 / 692/420 / Animal cognition / Animals / Ataxia / Autism / Autistic Disorder - complications / Autistic Disorder - genetics / Autistic Disorder - pathology / Autistic Disorder - physiopathology / Behavior / Behavior, Animal - drug effects / Cell Count / Cell Shape - drug effects / Cerebellum - drug effects / Cerebellum - pathology / Cerebellum - physiopathology / Complications and side effects / Grooming - drug effects / Grooming - physiology / Heterozygote / Humanities and Social Sciences / letter / Maze Learning - drug effects / Maze Learning - physiology / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / multidisciplinary / Mutation - genetics / Pathogenesis / Pathology / Physiological aspects / Proteins / Purkinje cells / Purkinje Cells - drug effects / Purkinje Cells - metabolism / Risk factors / Rodents / Rotarod Performance Test / Science / Science (multidisciplinary) / Sirolimus - pharmacology / Social aspects / Social behavior / Social interaction / Studies / Synapses - metabolism / TOR Serine-Threonine Kinases - antagonists & inhibitors / TOR Serine-Threonine Kinases - metabolism / Tuberous sclerosis / Tuberous Sclerosis - complications / Tuberous Sclerosis - genetics / Tumor Suppressor Proteins - deficiency / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Vocalization, Animal - drug effects / Vocalization, Animal - physiology