MHCI Inhibition of Neuronal Repair Responses

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DESCRIPTION (provided by applicant): In the immune system, MHCI is well known for its ability to suppress NK cell and T cell function, providing a key mechanism for preventing autoreactivity. MHCI expression in the CNS is generally low. However, MHCI expression is locally induced on neurons following kainate-induced seizures and CNS injury, and numerous studies have observed increases in MHCI expression in the CNS of patients with brain injury, stroke, epilepsy and neurodegenerative diseases. Recently, neuronal MHCI was shown to be involved in the elimination of inappropriate synaptic connections in the CNS. Moreover, our preliminary results indicate that MHCI can inhibit neuronal outgrowth in vitro. Based on these observations, we hypothesized that the induced expression of MHCI on neurons following injury might counteract neuronal repair responses in vivo. To test this hypothesis, we utilized a well-characterized model of compensatory neuronal sprouting that occurs following unilateral lesioning of the perforant path, combined with transgenic mice which were genetically engineered to express low levels of MHCI on CNS neurons. Our preliminary results indicate that although these transgenic mice had no apparent developmental CNS abnormalities, they have severely reduced compensatory sprouting responses following CNS injury. This proposal will further test the hypothesis that neuronal MHCI can inhibit compensatory neuronal sprouting responses. This will provide a foundation from which the role of MHCI in neurodevelopment and neuronal repair can be further assessed. This proposal opens a new area of research, the results of which may provide important conceptual advances. Conceivably, treatments that limit the neuroinhibitory effects of MHCI could lead to new clinical approaches to mitigate neuropathological disorders.