The cerebellum is primarily responsible for coordinating motor movement by processing and modifying descending motor commands from the cortex. General cerebellar circuitry is rather homogenous;however, considerable heterogeneity exists at distinct synaptic connections within this microcircuitry. Preliminary studies suggest there is more variability in the regulation of glutamate release at individual parallel fiber terminals than originally reported. The goal of this proposal is to better understan signaling properties of the parallel fibers through a careful study of individual parallel fiber - stellate cell synapses.
Aim 1 will investigate the source of glutamate responsible for activation o extrasynaptic NMDA receptors on the stellate cells. This work will identify whether action potential-dependent, synchronous release or action potential-independent, asynchronous release is the primary method of glutamate release required to elicit NMDA receptor currents. Using 2-photon laser uncaging of glutamate, Aim 2 will determine the extent of NMDAR activation by mimicking asynchronous and multivesicular release.
This Aim will also establish whether the NMDARs are localized perisynaptically or dispersed evenly throughout the stellate cell dendritic tree. Through a clearer understanding of cerebellar microcircuitry, we may potentially identify new therapeutic strategies for the treatment of cerebellar specific motor deficits.
The cerebellum is a critical component in the coordination of movement and motor learning. Extensive research has studied the primary neurons responsible for signal processing in the cerebellar cortex but less is known about the ancillary inhibitory interneurons that modify these signals. This project will investigate novel forms of signal processing by these support cells. The knowledge gained from this study may be used in the identification of future therapeutic targets for the treatment of motor disorders associated with the cerebellum.