Reduced synaptic clustering of GABA and glycine receptors in the retina of the gephyrin null mutant mouse

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Abstract
Clustering of neurotransmitter receptors in postsynaptic densities involves proteins that aggregate the receptors and link them to the cytoskeleton. In the case of glycine and GABAA receptors, gephyrin has been shown to serve this function. However, it is unknown whether gephyrin is involved in the clustering of all glycine and GABAA receptors or whether it interacts only with specific isoforms. This was studied in the retinae of mice, whose gephyrin gene was disrupted, with immunocytochemistry and antibodies that recognize specific subunits of glycine and GABAA receptors. Because homozygous (geph −/−) mutants die around birth, an organotypic culture system of the mouse retina was established to study the clustering of gephyrin and the receptors in vitro. We found that all gephyrin and all glycine receptor clusters (hot spots) were abolished in the geph (−/−) mouse retina. In the case of GABAA receptors, there was a significant reduction of clusters incorporating the γ2, α2, and α3 subunits; however, a substantial number of hot spots was still present in geph (−/−) mutant retinae. This shows that gephyrin interacts with all glycine receptor isoforms but with only certain forms of GABAA receptors. In heterozygous geph (+/−) mutants, no reduction of hot spots was observed in the retina in vivo, but a significant reduction was found in the organotypic cultures. This suggests that mechanisms may exist in vivo that allow for the compensation of a partial gephyrin deficit. J. Comp. Neurol. 427:634–648, 2000.