Major histocompatibility complex class I (MHC-I) molecules are well known for the important immune role that they perform in the presentation of viral and tumor antigens to circulating T lymphocytes. However, they also play a critical "non-immune" role in activity-dependent synapse elimination during development and in synaptic plasticity in the adult. Differences in various classical and non-classical MHC-I expression patterns suggests that specific MHC-I proteins may play regionally specific roles in the CNS. However, our knowledge of MHC-I function in the CNS is limited such that we do not know if classical and/or non-classical MHC-I proteins are selectively required for synapse elimination and/or synaptic plasticity. This application will take advantage of the unique synaptic circuitry of the cerebellum to compare and contrast the potential roles of classical and non-classical MHC-I molecules during normal cerebellar development and function at the single cell level. The specific aims of this study are designed to: 1) test the hypothesis that developmental changes in specific MHC-I expression patterns in the cerebellar cortex can be correlated with known patterns of synaptogenesis in the murine cerebellum; and 2) determine if blockade of classical or nonclassical MHC-I expression or signaling will result in impaired synapse elimination at the climbing fiber- Purkinje cell synapse and/or altered synaptic plasticity at the parallel fiber-Purkinje cell synapse in the adult cerebellum. These aims will be achieved using standard immunohistochemistry and in situ hybridization techniques (using MHC-I subtype specific antibodies and mRNA probes) in combination with electrophysiological recording of cerebellar Purkinje cells in cerebellar slices prepared from adult wildtype and selected knockout mice. The results of the proposed experiments will extend our limited knowledge of neuronal MHC-I expression and function within the CNS to include the cerebellum, an important structure involved in both motor control and cognition. More importantly, this study will begin to provide essential information on the specific non-immune roles that various classical and non-classical MHC-I proteins may play in the developing and adult CNS.

R03HD042199

2003-01-01

2005-12-31