GABAergic Innervation Organizes Synaptic and Extrasynaptic GABAAReceptor Clustering in Cultured Hippocampal Neurons

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Abstract
We have studied the effects of GABAergic innervation on the clustering of GABAA receptors (GABAARs) in cultured hippocampal neurons. In the absence of GABAergic innervation, pyramidal cells form small (0.36 ± 0.01 μm diameter) GABAAR clusters at their surface in the dendrites and soma. When receiving GABAergic innervation from glutamic acid decarboxylase-containing interneurons, pyramidal cells form large (1.62 ± 0.08 μm breadth) GABAAR clusters at GABAergic synapses. This is accompanied by a disappearance of the small GABAAR clusters in the local area surrounding each GABAergic synapse. Although the large synaptic GABAAR clusters of any neuron contained all GABAAR subunits and isoforms expressed by that neuron, the small clusters not localized at GABAergic synapses showed significant heterogeneity in subunit and isoform composition. Another difference between large GABAergic and small non-GABAergic GABAAR clusters was that a significant proportion of the latter was juxtaposed to postsynaptic markers of glutamatergic synapses such as PSD-95 and AMPA receptor GluR1 subunit. The densities of both the glutamate receptor-associated and non-associated small GABAAR clusters were decreased in areas surrounding GABAergic synapses. However, no effect on the density or distribution of glutamate receptor clusters was observed. The results suggest that there are local signals generated at GABAergic synapses that induce both assembly of large synaptic GABAAR clusters at the synapse and disappearance of the small GABAAR clusters in the surrounding area. In the absence of GABAergic innervation, weaker GABAAR-clustering signals, generated at glutamatergic synapses, induce the formation of small postsynaptic GABAAR clusters that remain juxtaposed to glutamate receptors at glutamatergic synapses.