A Novel Presynaptic Role for MHCI in Regulating Cortical Synapse Formation

Project Summary For years, researchers have observed evidence of cross–talk between the immune system and the nervous system, but the idea that immune molecules play non-immune roles in the brain in the absence of disease has only recently gained attention, due in large part to work focusing on the major histocompatibility complex I

(MHCI) molecules. In the central nervous system, MHCI is expressed in neurons and glial cells and regulates many aspects of development, including activity-dependent synaptic refinement, and synaptic and homeostatic plasticity. MHCI has also been implicated in mediating both genetic and environmental risk factors of a wide

range of brain diseases, including autism and schizophrenia. In addition to its well-documented roles in plasticity and disease, the McAllister laboratory recently demonstrated that MHCI molecules on neurons negatively regulate the establishment and function of connections onto cortical neurons. MHCI in the

postsynaptic cell clearly mediates some of this effect, but MHCI is also present in axons and in the presynaptic terminal and remarkably, there are no reports to date of any function for MHCI in these presynaptic compartments. Using a novel co-culture system, I have discovered that MHCI levels in presynaptic neurons

negatively regulate the number of synapses they form onto their targets. The central goal of my thesis is to determine whether, and how, MHCI molecules in presynaptic cortical neurons regulate the density of synapses formed onto their targets. In Aim 1, I will determine whether specific types of MHCI molecules

(H2-Kb and H2-Db) in presynaptic neurons negatively regulate the density and dynamics of synapses those neurons form with their targets in cortical cultures. Then, I will use a novel, innovative long-term imaging assay to measure the effect of MHCI on synapse dynamics in order to start to determine how MHCI in presynaptic

neurons negatively regulates synapse development. In Aim 2, I will determine whether activity regulates the density and dynamics of synapses a cell makes onto its targets, as well as whether the presynaptic effects of MHCI on synapse density are activity-dependent. Results from this project will provide new information about

the protein dynamics underlying synapse formation and elimination in early developing neural networks and will reveal novel cellular mechanisms mediating the effects of MHCI in neural development, including the first role for presynaptic MHCI In regulating synapse formation. My findings may thereby provide insight into how

novel therapies could be developed to alter MHCI signaling in the brain in the future to ameliorate neuro- immune-based disorders. These discoveries, together with the new techniques and career skills I will learn through my training plan, will position me optimally for a successful future career in neuroimmunology

research.