Project 2: Cellular and molecular mechanisms disrupted in 22q13 deletion syndrome and autism 

Funding: NIMH, Whitehall Foundation, NARSAD, Brain Research Foundation 

Mutations in genes encoding synaptic proteins and impaired functional brain connectivity are emerging as common deficits associated with autism spectrum disorders (ASDs). However, how mutated synaptic proteins affect the properties of human neurons at the cellular and molecular levels to cause abnormal brain connections remains an important unanswered question. Addressing this question is essential for understanding the etiology and pathology of ASDs and developing novel therapeutic strategies for patients. We previously demonstrated that SHANK3-deficient iPSC-derived cortical neurons, generated from 22q13 deletion syndrome patients with autism, have severely impaired intrinsic excitability and excitatory synaptic transmission (Shcheglovitov et al. Nature 2013). However, how these two phenotypes develop and affect neuronal connectivity in the brain remain unknown. The goal of this project is to elucidate the cellular and molecular mechanisms responsible for the development of synaptic and connectivity deficits in SHANK3-deficient human neurons.