This project will focus on the hypothesis that N-methyl-D-aspartate (NMDA) glutamate receptors and neuronal gap junctions act concertedly to determine the spatio-temporal dynamics of activity within electrically coupled networks in brain. The hypothesis will be tested in the inferior olive, a major afferent of the cerebellum that has the highest density of electrical synapses in the adult brain. Previous work from our laboratory showed that NMDA receptor activation induces high-threshold oscillations in membrane potential in inferior olive neurons and that neuronal gap junctions mediated by connexin36 are critical for the continuity and strength of coherent oscillations in the inferior olive. There are 4 aims. Aim 1 will determine whether NMDA receptors regulate electrical coherence and rhythm within a coupled network by acting on neuronal gap junctions in vivo. Aim 2 will determine whether NMDA receptors shape the spatial dynamics of electrical coupling in vitro. Aim 3 will determine whether there is a correspondence between NMDA receptor upregulation in the inferior olive and hypoxia-induced death of cerebellar neurons. Aim 4 will determine whether the block of NMDA receptor function in the inferior olive alone, or with neuronal gap junctions, will prevent delayed neuronal death in the cerebellum after hypoxia. These aims will be carried out with a combination of multielectrode recording, multibeam multiphoton microscopy, and gene transfer to express proteins with dominant-negative effect in the inferior olive. Recently, the upregulation of the NMDA receptor in the inferior olive and the death of Purkinje cells were independently related to sudden infant death syndrome. The research will establish how these clinically-relevant phenomena are related to one another.
NIH ExPorter
NIH ExPorter