AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

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PROJECT SUMMARY/ABSTRACT Activation of group 1 (Gp1) metabotropic glutamate receptors leads to robust elevation of intrinsic excitability of hippocampal excitatory neurons. Abnormally elevated activity of Gp1 mGluR, on the other hand, has been observed in multiple neurological disorders with comorbid epilepsy. Despite these observations, the mechanisms underlying elevated intrinsic excitability and seizure activity following activation of Gp1 mGluRs remain unclear. Through the support of the parent award, our recent studies discovered that the activity of tumor suppressor p53 is positively correlated with neuronal excitability in vitro and seizure susceptibility in vivo. Because our latest data showed an up-regulation of p53 protein levels and transcription activity upon Gp1 mGluR activation, we hypothesize that activation of Gp1 mGluRs promotes neuronal intrinsic excitability and seizure activity in part through p53. In Aim 1, we propose to study the molecular regulation of p53 activity following activation of Gp1 mGluR. In Aim 2, we propose to determine the contribution of p53 to Gp1 mGluR-induced elevation of neuronal intrinsic excitability. In Aim 3, we propose to evaluate the role of p53 in Gp1 mGluR- associated seizure activity in vivo. We expect this project to (1) provide training to a promising graduate student who came from a disadvantaged background, (2) elucidate the mechanism underlying activation of Gp1 mGluR- induced neuronal hyperexcitability, which is within the scope of Aim 2.3 of the parent award; and (3) broaden our fundamental understanding of p53 in the central nervous system, which is directly associated with Aim 3.3 of the parent award.