Description:

The Center for Autism and Neurodevelopment Welcomes Dr. Morgan Sheng 

Core Institute Member, Broad Institute of MIT and Harvard

Co-Director of the Stanley Center for Psychiatric Research at the Broad Institute
Professor of Neuroscience, Department of Brain and Cognitive Sciences

Affiliate Member, The Picower Institute for Learning and Memory
Affiliate Member, McGovern Institute for Brain Research

Abstract:

Schizophrenia and bipolar disorder are severe psychotic disorders whose neurobiological mechanisms of are poorly understood. Human genome sequencing has revealed rare loss-of-function genetic variants that greatly increase the risk of schizophrenia (SCHEMA gene mutations) and Bipolar Disorder (BiPex gene mutations). To gain insight into disease mechanism, we are investigating a panel of mouse mutants harboring SCHEMA and BiPex mutations using systematic unbiased approaches (transcriptomics, proteomics, behavior, EEG). These studies have uncovered widespread changes in synapses, disturbances in specific molecular pathways in diverse cell types, and convergent impact on particular brain regions and neuromodulatory systems. For instance, heterozygous mutation in the SCHEMA gene GRIN2A, encoding the NMDA receptor subunit GluN2A, not only affects glutamatergic synapses in prefrontal cortex but also causes a hyperdopaminergic state in the striatum, thereby unifying the "hypo-glutamate” and the “hyperdopaminergic” hypotheses of schizophrenia in a genetically valid animal model. Mouse mutants in Akap11 (a risk gene for both schizophrenia and bipolar) also show major disturbances in striatum, likely driven by elevated protein kinase A signaling.