Our lab studies how proteins of the immune system contribute to the formation, function, and modification of neuronal connectivity. We are particularly interested in members of the major histocompatibility complex class I (MHCI), a family of proteins that are best-known for their role in antigen presentation. We recently identified MHCI as an unexpected endogenous regulator of synaptic transmission mediated by NMDA-type glutamate receptors (NMDARs). In the adult hippocampus, we find that MHCI negatively regulates NMDAR-mediated synaptic transmission, and is required for normal NMDAR-dependent synaptic and behavioral plasticity. These studies define a new and critical role for MHCI in the healthy brain, and suggest a potential mechanistic basis for the striking genetic links between human MHCI genes and schizophrenia, a disorder in which NMDAR dysfunction figures prominently. Our ongoing studies aim to define the molecular mechanisms by which MHCI regulates NMDARs, to identify the upstream genetic and epigenetic factors that control MHCI expression in the nervous system, and to characterize MHCI’s downstream impacts on circuit structure and function. By understanding how MHCI contributes to normal brain development and plasticity, we hope to identify novel approaches for the diagnosis, treatment, and prevention of disorders of the developing and aging nervous system.