Tuberous Sclerosis Complex
Neural Circuits Underlying Autism Relevant Behaviors in TSC
Posted September 9, 2020
Peter Tsai, University of Texas, Southwestern Medical Center
Within the tuberous sclerosis (TSC) community there is a very high prevalence of autism spectrum disorders (ASDs) – often approaching 50%. ASDs are neuropsychiatric disorders characterized by social impairment and repetitive, restrictive, or inflexible behaviors. Despite the high prevalence in TSC and in the population at large, the underlying mechanisms remain poorly understood, and to date no targeted therapies exist for this disorder. Clinical studies have implicated dysfunction of the cerebellum in the pathogenesis of autism, and Dr. Tsai and his team have generated a TSC model which demonstrates that cerebellar dysfunction is sufficient to generate ASD behaviors. They have additionally shown that inhibition of a specific cerebellar domain, RCrusI, also generates ASD behaviors, while stimulation of this domain rescues social behaviors in the TSC mouse model. However, further research is needed to elucidate how this cerebellar domain regulates these behaviors.
With support from a Fiscal Year 2016 Idea Development Award, Dr. Tsai and his team aimed to study how the RCrusI domain regulates autism-relevant behaviors in TSC. They hypothesized that the RCrusl domain regulates these behaviors via modulation of cerebellar output nuclei, the deep cerebellar nuclei (DCN), and downstream neural circuit connections. Through this work they have identified that RCrusl largely targets the lateral, dentate nucleus (DN), with observations that activity in DN is increased in a PC-Tsc1 mouse model of TSC. Upon further evaluation of the anatomic pathways connecting these two regions, they also found that the connections between RCrusI and the parietal association cortex are mediated via the DN cerebellar output nucleus. They also identified rescue of social behaviors in multiple paradigms, including social approach and social olfaction testing, in PC-Tsc1 mice upon inhibition of the DN. However, unlike with social behaviors, they observed no evidence for rescue of repetitive and inflexibility behaviors. Together, these findings support the hypothesis that the parietal association cortex is mediating cerebellar regulated ASD behaviors in TSC and that modulation of parietal association cortex function is sufficient to rescue social behaviors in PC-Tsc1 mutant mice. These data point to the critical role of cerebellar-cortical circuits in the regulation of ASD-relevant behaviors in TSC and the ability to modulate behaviors (specifically, social behaviors) in mutant animals during adulthood. This raises the prospect that circuit modulation may provide a therapeutic opportunity for social behaviors and that this modulation might have potential benefit, even into adulthood. Ultimately, they hope these translational studies will lead to clinical benefit for individuals with TSC and potentially, ultimately to individuals with ASD even outside of TSC.
Last updated Wednesday, September 9, 2020