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Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome

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Tufts University School of Medicine Boston United States

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Our preliminary studies demonstrate that Fmr1 KO mice at p21 have a decrease in phosphorylation of S443in the 4 subunit compared to WT and an increase in the phosphorylation of 3 subunits at the S408409site compared to WT. We have previously showed that phosphorylation of these residues changes the trafficking of the subunits so the changes observed in Fmr1 KO mice would predictably have consequences for trafficking of these essential inhibitory subunits. We noted that there was a significant decrease in tonic inhibition in dentate gyrus granule cells in p21 Fmr1 KO mice compared to WT. A 10 min exposure to neuroactive steroids followed by a 30 min wash induced a 3 fold increase in tonic current in Fmr1 KO animals which was prevented with PKC inhibition. Using a perforated multi-electrode array we have observed in cortical-hippocampal slices seizure like events SLE propagating through the dentate gyrus and into the CA3 and CA1 regions of the hippocampus of Fmr1 KO mice but in WT mice SLEs did not propagate through the dentate gyrus. We predict the increase neuronal excitability seen in Fmr1 KO mice is due to the deficits in tonic inhibition.

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Technical Report,15 Jul 2015,14 Jul 2016



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