Impact of conformationally specific human anti-NMDA receptor antibodies on NMDA receptors and neuronal function

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Project Summary The goal of the proposed 5-year training program is the development of the applicant’s independent research career as an academic neurologist focused the mechanisms underlying autoimmune neurologic disorders associated with autoantibodies against synaptic components. Dr. Panzer completed residency training in Pediatric Neurology, clinical fellowship training in Movement Disorders and has joined the neurology faculty at the Children’s Hospital of Philadelphia (CHOP) focusing on the care of children afflicted with these disorders. Her near-term goals are to develop and refine the essential skills of experimental design, data interpretation, grant writing, and lab management that will be required to successfully transition to a career as an independent physician-scientist. The focus of her research program will be to define the effects of patient derived antibodies on synaptic and circuit function. Dr. David Lynch, an expert in N-methyl-D-aspartate receptor (NMDAR) biology and co-discoverer of the autoimmune disease anti-NMDAR encephalitis, will be her scientific mentor. Dr. Douglas Coulter, an expert in the optical imaging of neuronal circuit activity with be her co-mentor. In addition, a group of eminent physicians and scientists has been assembled to serve on a Scientific Advisory Committee to support her career development. She will draw upon their expertise and the outstanding and highly collaborative training environment and resources available at CHOP and the University of Pennsylvania as she advances toward her goal of becoming an academic neurologist and translation neuroscientist. The research goal of this proposal is to determine autoantibody mechanisms in anti-NMDAR encephalitis, an autoimmune brain disorder. Chronic treatment of neurons with these antibodies results in loss of NMDARs, an important brain neurotransmitter receptor, and reduced synaptic NMDAR currents. Despite this understanding, some features of anti-NMDAR encephalitis, such as seizures, are unexplained. Better understanding of this disease is critical for the development of new non-immunosuppressive therapies. The central hypothesis of this proposal that patients’ antibodies have unique conformational specificity and agonist effects, resulting in NMDAR dysfunction of select active neuronal circuits, rather than global receptor knockdown. This proposal will establish the role of the open conformation of the NMDAR in antibody binding, define the binding and effects of antibodies on NMDARs at synaptic and extrasynaptic sites, and map the cell-type specific and circuit level effects of anti-NMDAR antibodies.