Project 3: Mechanisms of epilepsy in human neurodevelopmental disorders: focus on 22q13 deletion syndrome 

Funding: NINDS

Epilepsy is a complex neurological condition associated with many genetic neurodevelopmental disorders, including Fragile X, Rett, Angelman, and 22q13 deletion syndromes. Although we know the causative genetic abnormalities for most of these disorders, whether and how the disrupted genes induce the development of overexcitable neuronal networks and contribute to epilepsy remain largely unknown. We previously demonstrated that SHANK3-deficient iPSC-derived cortical neurons generated from 22q13 deletion syndrome patients have increased intrinsic excitability due to significantly elevated input resistance (Shcheglovitov et al. Nature 2013). This phenotype could potentially contribute to the development of epilepsy in patients. The goal of this project is to determine whether and how the loss of SHANK3 causes the development of overexcitability deficits in human cortical tissue using cortical organoids generated from control and SHANK3-deficient iPSCs.