The mammalian neocortex is our most complex organ and plays an indispensable role in many human behaviors. Impaired function of cortical circuits are central to a diverse set of neurological and psychiatric diseases including autism spectrum disorders, epilepsy, schizophrenia and Alzheimer’s disease. Despite their functional and clinical importance, the cell types that comprise the neocortex and the molecular mechanisms that specify their properties and connectivity are only partly understood. We study the development and function of the neocortex in the laboratory mouse using a combination of genetic, genomic and electrophysiological approaches. Questions that we focus on include: “What genetic and epigenetic mechanisms allow different cell types to develop different patterns of connectivity?” “How does activity regulate the cell type-specific expression of neuronal ion channels and synaptic molecules” and “How do genetic lesions that produce disease in mice and humans alter cellular physiology and gene expression?”
In our approach to examining the neocortex we use new driver strains developed here and by our collaborators to genetically or virally deliver mutant alleles to specific neuronal cell types. We monitor effects on physiology and connectivity using patch clamp recording and high resolution anatomy. To evaluate changes in gene expression we developed methods for manually sorting fluorescent neurons and performing genome-wide expression profiling. Using these approaches we have discovered some of the ion channels that mediate specific firing properties of cortical neurons and have identified physiological and molecular mechanisms that cause cortical impairment in the autism spectrum disorder Rett Syndrome. Current projects are focused on the role of cell adhesion molecules in regulating connectivity, the importance of DNA methylation for maintaining neuronal cell identity, and the molecular mechanisms of circuit homeostasis.