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Dendritic Potassium Channel Regulation by Fragile X Mental Retardation Protein (FMRP)

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Fragile X syndrome (FXS) is a common form of mental disability and one of the known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeats that leads to DNA methylation of the fragile X mental retardation gene 1 (FMR1) and transcriptional silencing, resulting in the absence of fragile X mental retardation protein (FMRP), an mRNA binding protein. Although it is widely known that FMRP is critical for metabotropic glutamate receptor (mGluR)-­‐ dependent long-­‐term depression (LTD), which has provided a general theme for developing pharmacological drugs for FXS , specific downstream targets of FMRP may also be of therapeutic value. Since alterations in potassium channel expression level or activity could underlie neuronal network defects in FXS , we will describe our recent findings on how the dendritic potassium channel, Kv4.2 might be altered in mouse models of FXS and the possible therapeutic avenues for treating FXS . How transmitter receptors modulate neuronal signaling by regulating voltage-­‐gated ion channel expression remains an open question. Recently we reported dendritic localization of mRNA of Kv4.2 voltage-­‐gated potassium channel, which regulates synaptic plasticity, and its local translational regulation by FMRP . FMRP suppression of Kv4.2 is revealed by elevation of Kv4.2 in neurons from fmr1 knockout (KO) mice, and in neurons expressing Kv4.2-­‐3’UTR that binds FMRP . Moreover, treating hippocampal slices from fmr1 KO mice with Kv4 channel blocker restores long-­‐term potentiation (LTP) induced by moderate stimuli. The evaluation of Kv4.2 potassium channels as potential therapeutic targets for FXS will allow us to be extended to include additional proof-­‐of-­‐principle tests for genetic reduction of Kv4.2 as potential ways to reduce fmr1 KO mutant phenotypes, with a strong interest in pursuing translational research to develop treatments and improve outcomes for individuals with FXS .

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