Glutamate, the major excitatory transmitter in the central nervous system, is crucial not only for synaptic transmission but also for long-term neuronal changes such as synaptic plasticity and control of gene expression. However, excessive release of glutamate (as occurs in pathological situations) can result in cell death and NMDA receptor hypofunction has been implicated in schizophrenia. Recently, in collaboration with Dr. Josep Dalmau, we have found that antibodies to the NMDA receptor mediate an immune encephalitis associated with personality and behavioral changes, acute psychosis, and short-term memory deficits. Individuals with this syndrome make antibodies that selectively react with the hippocampus, an area involved in memory, and the antigen is the NR1 subunit of the NMDAR. Using molecular biological approaches we have defined the epitope to be within the first 380 amino acids on NR1. Furthermore, creation of the epitope is blocked by tunicamycin and disruption of a specific N- linked glycosylation/deamidation site in NR1 removes immunoreactivity, suggesting that site specific N-linked glycosylation and deamidation are specifically involved in the production of the epitope. We will characterize the features of this epitope in order to better understand the role of these 2 crucial biochemical processes in NMDAR properties. We will ascertain the distribution of deamidated and differentially glycosylated NMDA receptors in the brain and comparing this to the unique pattern of patients'related anti-NMDAR immunoreactivity that is found in anti NMDA receptor encephalitis. In addition, we will immunolabel NMDAR with patient serum and assess whether labeled NMDAR are glycosylated or deamidated at specific sites. In our second aim, we introduce NMDA receptors into cell lines lacking specific glycosylation enzymes. We will then assess the effect on the glycosylation pattern of NMDAR, on their cellular trafficking, and their physiological properties. These will be compared to the unique properties of NMDAR in specific brain regions and cell types. Together, these aims will supply new data on the mechanisms involved in antiNMDAR encephalitis, provide new understanding of the role of glycosylation and deamidation in neuronal chemistry, and devise new strategies for studying the biochemistry of NMDA.
The proposal addresses the mechanisms by which antibodies are generated in the disorder known as anti-N-methyl-D-aspartate Receptor encephalitis. Through understanding of this process, the proposal may facilitate therapies for preventing damage in this disorder and a basic understanding of other neurologic disorders such as stroke.
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|Gleichman, Amy J; Spruce, Lynn A; Dalmau, Josep et al. (2012) Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain. J Neurosci 32:11082-94|