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Identification of Critical Periods for Treatment of Autistic Behavior in Purkinje Cell Tsc1 Mice
Cerebellar Dysfunction has been implicated in the pathogenesis of autism spectrum disorders. By generating a mouse model where Tsc1is deleted specifically in cerebellar Purkinje Cells, we have recently demonstrated that cerebellar dysfunction is sufficient to generate abnormal autistic behaviors and that early treatment with the mTOR inhibitor rapamycin can prevent the development of cerebellar pathology and autistic-like behavior.
Objectives:
Evaluate the benefits of later rapamycin treatment on autistic-like behaviors and to delineate critical periods of treatment for autistic-like behaviors.
Methods:
Using our Purkinje Cell Tsc1mouse mutants, we have investigated the impact of rapamycin treatment initiated during adulthood on behavior, pathology, and electrophysiologic function to delineate the critical periods of treatment of autistic behavior.
Results:
With rapamycin treatment starting at 6 weeks, we have demonstrated rescue of motor learning deficits and social behaviors – but not repetitive behaviors or cognitive inflexibility – in Purkinje Cell Tsc1mutant mice. Rapamycin treatment at this time point also rescues pathologic and electrophysiologic deficits in these mice. Later initiation of treatment at 10 weeks results in continued rescue of motor learning, but with inability to rescue social or repetitive behaviors. Moreover, pathologic deficits are also not ameliorated with treatment at this time point.
Conclusions:
These findings demonstrate that later treatment – even into adulthood – might offer benefit for social impairments. Furthermore, we demonstrate a critical period for treatment of social behaviors that differs from the critical period of rescue for motor learning, repetitive behaviors, and cognitive inflexibility, providing a platform for investigating the mechanisms underlying the critical periods for these behaviors and for further investigating the cerebellar contribution to autistic behavior.