The unipolar brush cell (UBC) is a newly discovered interneuron situated in the granular layer of the mammalian cerebellum. It receives excitatory synaptic input on the dendritic brush from a single mossy fiber (MF) terminal in the form of a giant glomerular glutamatergic synapse. This synapse is provided with an unusually prominent apparatus of actin filaments, which link the postsynaptic density with the dendritic core. The importance of the UBC in the context of cerebellar function has recently been highlighted by several recent discoveries. l) While UBCs in rodents are largely restricted to the vestibulocerebellum, in higher mammals, including man, they expand to populate the entire vermis, the intermediate cortex, and to some extent also the hemispheres. 2) The UBC axons form a system of intrinsic mossy fibers in the granular layer that branch to give rise to terminal rosettes that synapse with both granule cell and UBC dendrites within glomeruli. Single mossy fiber stimuli evoke a prolonged burst of firing in UBCs, which will thus be distributed to postsynaptic targets within the granular layer. We hypothesize that the synaptic excitation of UBCs by extrinsic MFs will drive a large ensemble of granule cells, and thus will contribute a powerful form of distributed excitation within the basic circuit of the cerebellar cortex of great significance for information processing in the human cerebellum. The present specific aims deal specifically with: (l) the properties of transmission at UBC-UBC glomeruli; (2) the actin anchoring of GluRs; and (3) the development of the UBC-UBC synapse. These studies will be primarily performed on slice- cultures of the isolated mouse nodulus (lobulus X). This preparation, which was developed during the last two years in the laboratory of the P.I., has made it possible for the first time to analyze, both structurally and functionally, the synapses formed by UBC axons on granule cells and other UBCs by a combination of confocal immunofluorescence, electron microscopic and patch-clamp recording methods. We therefore propose a multidisciplinary approach to the study of this newly discovered cerebellar network. Through a combination of approaches at the ultrastructural and cellular physiological levels, we will rigorously examine the fundamental mechanisms of regulation and function, regulation, and development of this pathway. The results will provide new insights into information processing in the cerebellum of fundamental importance to our understanding of motor control.
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