CALCIUM-PERMEABLE AMPA RECEPTORS AND MOTONEURON SURVIVAL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ca2+ influx through ionotropic glutamate receptors constitutes one main source of Ca2+ entry required for activity-dependent regulation of early embryonic development. NMDA receptors were originally thought to be the sole source of Ca2+ influx through glutamate receptors; however, AMPA receptors also allow a significant influx of Ca2+ ions. The Ca2+ permeability of AMPA receptors is regulated by the insertion of at least one edited GluR2 subunit, which significantly reduces the Ca2+ permeability. Using the chick spinal cord as a model, we have demonstrated that AMPA receptors are Ca2+ permeable at early stages of motoneuron development. However, AMPA receptors become Ca2+ impermeable by embryonic day 11, when differentiation of the hindlimb neuromuscular system is virtually complete with functional synapses and contractile muscles capable of generating spontaneous contractions. The developmental switch in the Ca2+ permeability of AMPA receptors is triggered by increased GluR2 expression in motoneurons. Thus, the question arises what is the developmental role of transiently expressed, Ca2+-permeable AMPA receptors at early stages of spinal cord development. We hypothesize that GluR2 expression by E8 will promote motoneuron survival by dampening Ca2+ influx through AMPA receptors. Here we propose to pursue the following specific aim: to test whether downregulation of GluR2 expression disrupts the normal pattern of motoneuron survival in vivo.