Impact of human anti-NMDA receptor antibodies on glutamate receptor signaling, calcium mobilization, and hippocampal neuronal circuits in autoimmune encephalitis

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This is a proposal for a five year research career development program focused on the study of human antibodies binding to neuronal cell surface proteins in autoimmune encephalitis. The goal is to gain understanding of the pathophysiology of autoimmune encephalitis and identify novel targets for therapy in neurological disease. The principal investigator, David R. Benavides, M.D., Ph.D., is an Assistant Professor of Neurology at University of Maryland School of Medicine. My long term career goal is to become an independent investigator in translational research focused on immune regulation of neural function in neurological disease. To accomplish this goal, I propose a research project and training plan in proteomics, advanced live cell microscopy, and in vivo miniscope technology, which is integral to addressing the central research question posed here. The research project builds on my previous research in signal transduction and molecular neuroscience and clinical experience in neuroimmunology and integrates innovative approaches in areas of expertise represented by my mentor team at University of Maryland School of Medicine. I propose a comprehensive development plan, combining didactic instruction overseen by my mentors, formal coursework, applied training experiences with individual advisors, and participation in seminars and workshops. The proposed project and development plan will position me with a unique skillset that will enable me to transition to independence as a physician-scientist in translational neuroscience research. Encephalitis is a brain disease with significant morbidity and mortality. Anti-NMDA receptor (NMDAR) encephalitis is the most common form of autoimmune encephalitis and accounts for nearly 4% of all cases of encephalitis. Excitatory synaptic transmission and plasticity in the central nervous system are governed, in part, by a class of glutamate neurotransmitter receptors known as NMDARs. NMDAR dysfunction can cause psychosis, impaired memory, agitation, movement disorders, seizures, and coma and may result from many conditions, such as drug use, genetic predisposition, and antibody targeting (e.g., anti-NMDAR encephalitis). The effects of NMDAR antibodies on brain function in autoimmune encephalitis remain incompletely defined. My preliminary data show that NMDAR antibodies alter neuronal signaling and neuronal activity in primary rodent dissociated neuron cultures. How exactly NMDAR antibodies do this in anti-NMDAR encephalitis is a question that this proposal begins to address. Specifically, the aims of the proposal are: 1) define the effects of NMDAR antibodies on glutamate receptor signaling pathways, 2) determine the effects of NMDAR antibodies on neuronal calcium mobilization, and 3) determine the effect of NMDAR antibodies on hippocampal neuronal circuits in vivo. Our long term goal of this work is to elucidate the effects of human NMDAR antibodies in autoimmune encephalitis to advance novel therapeutics for neurological disease.