Function and Property of Extrasynaptic NMDAR in Neuronal Cell Death

Michigan State University, East Lansing MI

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Abstract

DESCRIPTION (provided by applicant): Overactivation of N-methyl D-aspartate receptor (NMDAR) by massive glutamate release during acute brain insults represents a major mechanism for neuronal loss in ischemic stroke and brain trauma. While proper activation of NMDAR is required for cell survival, overactivation of NMDAR stimulates cell death signaling and causes the loss of calcium homeostasis. There are significant interests and needs to target NMDAR as therapeutic interventions for ischemic stroke and other forms of neurodegeneration. Because general suppression of all NMDAR function may be detrimental to normal brain functions, targeting specific pools or subtypes of NMDAR may improve the therapeutic values. For example, inhibiting extrasynaptic NMDAR may attenuate receptor overactivation without disrupting normal synaptic functions. We hypothesize that the pharmacological property is dramatically different between synaptic and extrasynaptic NMDAR. To test the hypothesis and better understand the function of extrasynaptic NMDAR function, we will pursue 3 specific aims: Aim 1) Determine the function of extrasynaptic NMDAR in cell death;Aim 2) Determine the function of extrasynaptic NMDAR in Ca dysregulation;Aim 3) Determine the difference in pharmacological property between extrasynaptic and synaptic NMDAR. This application proposes to use calcium imaging and molecular characterization to identify the function and property of extrasynaptic NMDAR. The outcome of this proposal is expected to set the foundation for future therapeutic strategies to attenuate neurodegeneration, such as stroke, via specific blockade of extrasynaptic NMDAR. PUBLIC HEALTH RELEVANCE: Stroke is one of the major causes of mortality and adult disability in the United States. The long-term goal of our research is to develop molecular therapies for stroke. In addition, our study on molecular and cellular mechanisms may also lead to therapeutic development for other forms of neurodegeneration.