A fundamental question in molecular neuroscience is: how are properties of synapses (basic units of information storage) defined, formed, stabilized, maintained and modulated? Synaptic cell-adhesion molecules likely play critical roles at the synapse because they: i.) transsynaptically interact, in a poorly understood combinatorial manner, to physically couple the presynaptic axon and postsynaptic dendrite; and ii.) recruit key synaptic molecules (e.g. ion channels, ligand-gated receptors, scaffolding proteins) and/or initiate intracellular signaling cascades (e.g. kinases and small GTPase) in their respective cell. Thus, it is not surprising that genomic abnormalities in genes that encode for these molecules are frequently associated with neuropsychiatric disorders (Autism spectrum disorders (ASDs), schizophrenia, attention deficit/hyperactivity disorder and intellectual disability) and addiction (cocaine, opioid, alcohol and nicotine). It is essential to understand how synaptic cell-adhesion molecules are utilized in disease-relevant circuitry and how their dysfunction can contribute to the synaptic etiologies that underlie mental health disorders. Recent technological advances now allow the study of molecule function in distinct neural circuits with cell-type- and synapse-specific resolution to ultimately gain greater insight into how synaptic cell-adhesion molecules function.
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.