Our laboratory is interested in interrogating how synaptic cell-adhesion molecules function to shape cell-type- and synapse-specific synaptic transmission properties in the context of disease-relevant neural circuitry. Specifically, we are currently interested in dissecting the function of a family of essential presynaptic molecules called the neurexins. The mammalian genome houses three evolutionarily conserved, and structurally similar, neurexin genes (Nrxn1-3) that are frequently altered in human patients with mental health disorders. Interestingly, mutations unique to Nrxn3 are associated with both drug addiction and schizophrenia, which strongly suggests that neurexin-3 plays a dominant and non-redundant function to shape synapse functions in circuits implicated in both disorders. Schizophrenia and addiction are thought to share similar pathophysiological features - namely hyperactivity of the dopamine system. We will test the hypothesis that neurexin-3 (and other synaptic cell-adhesion molecules) plays a unique and dominant function at synapses in neural circuits that regulate dopamine levels in the brain.
We utilize cutting-edge multidisciplinary techniques that include: acute slice electrophysiology, animal behavior, stereotaxic injection of virus into targeted brain regions, functional circuit tracing viruses, optogenetics, molecular biology, mouse genetics and fixed and live cell imaging to dissect disease-relevant circuitry with unparalleled cell-type and synapse specific resolution. We are also keenly interested in applying single-cell next generation RNA sequencing (RNAseq) approaches to gain a molecular handle on poorly understood cells in the hippocampal formation and in the striatum. We hope that RNAseq will also identify candidate cell-adhesion molecules for future studies, where we will test function by applying CRISPR/cas9 technology to acutely alter candidate gene expression.