| First Author | Zhang N | Year | 2017 |
| Journal | Exp Neurol | Volume | 297 |
| Pages | 168-178 | PubMed ID | 28822839 |
| Mgi Jnum | J:261241 | Mgi Id | MGI:6153096 |
| Doi | 10.1016/j.expneurol.2017.08.008 | Citation | Zhang N, et al. (2017) Decreased surface expression of the delta subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome. Exp Neurol 297:168-178 |
| abstractText | While numerous changes in the GABA system have been identified in models of Fragile X Syndrome (FXS), alterations in subunits of the GABAA receptors (GABAARs) that mediate tonic inhibition are particularly intriguing. Considering the key role of tonic inhibition in controlling neuronal excitability, reduced tonic inhibition could contribute to FXS-associated disorders such as hyperactivity, hypersensitivity, and increased seizure susceptibility. The current study has focused on the expression and function of the delta subunit of the GABAAR, a major subunit involved in tonic inhibition, in granule cells of the dentate gyrus in the Fmr1 knockout (KO) mouse model of FXS. Electrophysiological studies of dentate granule cells revealed a marked, nearly four-fold, decrease in tonic inhibition in the Fmr1 KO mice, as well as reduced effects of two delta subunit-preferring pharmacological agents, THIP and DS2, supporting the suggestion that delta subunit-containing GABAARs are compromised in the Fmr1 KO mice. Immunohistochemistry demonstrated a small but statistically significant decrease in delta subunit labeling in the molecular layer of the dentate gyrus in Fmr1 KO mice compared to wildtype (WT) littermates. The discrepancy between the large deficits in GABA-mediated tonic inhibition in granule cells in the Fmr1 KO mice and only modest reductions in immunolabeling of the delta subunit led to studies of surface expression of the delta subunit. Cross-linking experiments followed by Western blot analysis demonstrated a small, non-significant decrease in total delta subunit protein in the hippocampus of Fmr1 KO mice, but a four-fold decrease in surface expression of the delta subunit in these mice. No significant changes were observed in total or surface expression of the alpha4 subunit protein, a major partner of the delta subunit in the forebrain. Postembedding immunogold labeling for the delta subunit demonstrated a large, three-fold, decrease in the number of symmetric synapses with immunolabeling at perisynaptic locations in Fmr1 KO mice. While alpha4 immunogold particles were also reduced at perisynaptic locations in the Fmr1 KO mice, the labeling was increased at synaptic sites. Together these findings suggest that, in the dentate gyrus, altered surface expression of the delta subunit, rather than a decrease in delta subunit expression alone, could be limiting delta subunit-mediated tonic inhibition in this model of FXS. Finding ways to increase surface expression of the delta subunit of the GABAAR could be a novel approach to treatment of hyperexcitability-related alterations in FXS. |
