This project will focus on the importance of neuronal synchrony and oscillation within the inferior olive, one of the two major afferent systems of the cerebellum. The inferior olive has the highest density of electrotonic synapses and gap junctions in the adult mammalian brain, but their function remains elusive. Our studies will employ a novel genetic tool involving a point-mutation in connexin36 - the protein that assembles neuronal gap junctions - that acts in a dominant-negative manner in vivo to prevent intrinsic connexin36 from assembling gap junctions in dendritic spines of olivary neurons. The basic working hypothesis is that electrotonic synapses among inferior olivary neurons are fundamental for cerebellar coordination of movement. There are four specific aims. Aim I will determine whether inhibition of connexin36-mediated gap junctions blocks inferior olivary neurons' sub-threshold oscillations in membrane potential and remediates a pathological tremor. Aim 2 will determine how inhibition of connexin36-mediated gap junctions within the inferior olive will alter synchrony and neuronal interaction within cerebellar cortex. Aim 3 will determine whether inhibition of neuronal synchrony within the inferior olive will alter the timing and trajectory of a spatially-guided movement involving a conditioned tongue protrusion behavior. Aim 4 will determine whether blockade of connexin36 mediated gap junctions within the inferior olive will prevent the death of Purkinje cells after brain ischemia. The research will provide fundamental information regarding the role of neuronal synchrony in motor control and for driving Purkinje cells into death after brain ischemia. Moreover, the research is likely to provide a greater understanding of essential tremor, which has been associated with pathological inferior olivary oscillation