Chemicogenetic rescue of autism-like social deficits in Shank3-deficient mice A hallmark for autism spectrum disorders (ASD) is social deficits and restricted & repetitive behaviors. Presently, there is no known cure for ASD. The goal of this R03 proposal is to find a novel, mechanism-based intervention for potential treatment of ASD in a mouse model. ASD are often associated with abnormalities of the N-methyl- D-aspartate (NMDA) receptors function. Haploinsufficiency of the Shank3 gene due to deletion or de novo mutation has been linked to autism in human genetics studies. Our recent studies showed Shank3-deficient mice exhibit autism-like social deficits and restricted & repetitive behaviors, as well as the significantly diminished NMDA receptors synaptic function in prefrontal cortex (PFC), a brain region controlling high-level ?executive? functions, all of which are impaired in ASD. We hypothesize that using the chemicogenetic technology to elevate PFC pyramidal neuronal activity will rescue autism-like social and diminished NMDA receptors synaptic deficits in Shank3-deficient mice. To test this, combined electrophysiological, behavioral, molecular and biochemical approaches will be used to address two important questions: (1) Does chemicogenetic elevating the synaptic activity of PFC pyramidal neurons rescue autism-like behavioral and synaptic deficits in Shank3-deficient mice? (2) What are the molecular mechanisms underlying the rescuing effect of chemicogenetic activation of PFC pyramidal neurons on autistic deficits in Shank3-deficient mice? Results gained from this study will help to identify molecular and cellular targets for the design of novel therapeutic strategies for ASD.
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impaired social communication and repetitive & restricted behavioral patterns. An extremely urgent undertaking in ASD studies is to discover novel, mechanism-based interventions for this devastating mental disorder that currently lacks effective treatment. This proposal will test our hypothesis that using the chemicogenetic technology to elevate PFC pyramidal neuronal activity will rescue autism-like social and synaptic deficits in Shank3-deficient mice, thus advancing our understanding the potential mechanisms and help to identify molecular and cellular targets for the design of novel therapeutic strategies for ASD and related disorders.