The long term goal of this research is to learn how experience during brain development, mediated by the activity-driven functioning of neural circuits, is translated into lasting structural change in synaptic connectivity. The specific goal of this research proposal is to examine the hypothesis that activity-dependent synaptic remodeling in development, and adult synaptic plasticity, involve a large gene family with well-known function in the immune system: MHC Class I genes (HLA genes in humans). Neuronal MHC Class I mRNA expression was discovered unexpectedly in an unbiased PCR-based differential screen for genes regulated by neural activity; initial genetic studies in mice lacking MHC I function then revealed a requirement for Class I MHC in visual system development and hippocampal plasticity (Huh et al, 2000). The goal of research proposed here is to learn more about how Class I MHC functions in the normal, uninjured CNS.
Three specific aims are proposed. 1) Determine whether MHC Class I protein in neurons is located at synapses and whether there is a molecular logic to expression patterns of MHCI family members by means of immunohistochemistry, RT-PCR of specific brain regions, and in situ hybridization to examine CNS expression. 2) Determine how MHC Class I functions in bidirectional synaptic plasticity in the hippocampus by standard microelectrode recordings and biochemical assessment of glutamate receptor trafficking in hippocampal slices from wildtype, loss (B2m/TAP1) and gain of function (NSE-Db) mutant mice. 3) Determine if Class I MHC is necessary for the translation of neural activity into lasting anatomical change at synapses by examining structure and physiology of synapses in wild type and mutant hippocampal neurons in vitro following pharmacological manipulations that alter neural activity. The results of these experiments should broaden our understanding of how use-dependent changes, both in development and in adult, are encoded in the structure of neural circuits. Changes in synapses and circuits occur during critical periods of learning in childhood, as well as in memory formation throughout life. Understanding the molecules and mechanisms involved is also crucial for addressing and ultimately curing disorders of learning and memory, from Dyslexia, Autism and other learning disorders, to Alzheimer's and other memory disorders of the aging brain.
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