How does loss of SHANK3 in human neurons affect neuronal connectivity in the brain?
Genetic abnormalities in synaptic proteins and abnormal brain connectivity are common in individuals with autism spectrum disorders (ASDs). However, whether and how autism-related mutations cause abnormal 5 connectivity in the brain is unknown. I previously characterized deficits in excitatory synaptic transmission in neurons derived from induced pluripotent stem cells (iPSCs) acquired from patients with ASDs. These deficits were largely caused by loss of a single copy of the gene encoding SHANK3, a postsynaptic density scaffolding protein of excitatory synapses. The goal of this project is to determine whether loss of SHANK3 in human neurons affects their structural and functional integration into neuronal circuits of the brain. I hypothesize that the loss of SHANK3 in human iPSC-derived neurons will result in the loss of specific neuronal inputs on these neurons when grafted into the prefrontal cortex of the mouse brain. I will test this hypothesis by transplanting SHANK3-deficient iPSC-derived neurons from patients with ASDs into mouse brains and determining whether these cells establish abnormal synaptic connections with local and remote brain regions. This study will substantially advance our understanding of the molecular, cellular, and circuitry deficits associated with ASDs and provide information for the development of new therapeutic strategies for ASD patients.