Transcriptional Mechanism underlying Neuronal Hyperexcitability in FXS

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PROJECT SUMMARY/ABSTRACT Fragile X syndrome (FXS) patients show multiple symptoms associated with neuronal, synaptic, and circuit hyperexcitability, such as sensory hypersensitivity, anxiety, and seizures. Although multiple mechanisms have been proposed to explain hyperexcitability in FXS, an effective treatment remains unavailable, indicating the need for search for more specific therapeutic strategy. It is well accepted that exaggerated activity of Group 1 metabotropic glutamate receptors (Gp1 mGluRs) contributes in part to the hyperexcitability in FXS. Activation of Gp1 mGluRs has been shown to lead to robust elevation of intrinsic excitability of hippocampal excitatory neurons and seizure susceptibility in mice. Despite these observations, the molecular regulation and mechanisms underlying elevated neuronal excitability following activation of Gp1 mGluRs have been complex and remain unclear. To improve our understanding of Gp1 mGluR-associated neuronal hyperexcitability in FXS, our preliminary observations led us to study the tumor suppressor p53. 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 data showed that activation of Gp1 mGluR leads to activation of p53, and the transcription activity of p53 is basally elevated in the FXS mouse model, the Fmr1 KO mice, we hypothesize that activation of Gp1 mGluR promotes neuronal intrinsic excitability in part through p53-dependent gene transcription, and inhibition of p53 can ameliorate neuronal excitability defects in FXS. To test this hypothesis, we propose in Aim 1 to study the mechanism by which p53 contributes to Gp1 mGluR activation-induced elevation of neuronal excitability. We will follow by pharmacologically or genetically inhibiting p53 in Aim 2 to determine whether the hyperexcitability phenotypes in Fmr1 KO mice can be ameliorated. We expect our research as proposed will provide a new aspect to our understanding of FXS. In addition, with the deep knowledge of p53 in the field of cancer biology and our preliminary data identifying neuron-enriched target genes of p53, the proposed research has the potential to introduce many new concepts into the design of future treatment for FXS.