Differential role of GABAA receptors and neuroligin 2 for perisomatic GABAergic synapse formation in the hippocampus

Abstract

Perisomatic GABAergic synapses onto hippocampal pyramidal cells arise from two populations of basket cells with different neurochemical and functional properties. The presence of the dystrophin-glycoprotein complex in their postsynaptic density (PSD) distinguishes perisomatic synapses from GABAergic synapses on dendrites and the axon-initial segment. Targeted deletion of neuroligin 2 (NL2), a transmembrane protein interacting with presynaptic neurexin, has been reported to disrupt postsynaptic clustering of GABA_A receptors (GABA_AR) and their anchoring protein, gephyrin, at perisomatic synapses. In contrast, targeted deletion of Gabra2 disrupts perisomatic clustering of gephyrin, but not of α1-GABA_AR, NL2, or dystrophin/dystroglycan. Unexpectedly, conditional deletion of Dag1, encoding dystroglycan, selectively prevents the formation of perisomatic GABAergic synapses from basket cells expressing cholecystokinin. Collectively, these observations suggest that multiple mechanisms regulate formation and molecular composition of the GABAergic PSD at perisomatic synapses. Here, we further explored this issue by investigating the effect of targeted deletion of Gabra1 and NL2 on the dystrophin-glycoprotein complex and on perisomatic synapse formation, using immunofluorescence analysis with a battery of GABAergic pre- and postsynaptic markers. We show that the absence of α1-GABA_AR increases GABAergic synapses containing the α2 subunit, without affecting the clustering of dystrophin and NL2; in contrast, the absence of NL2 produces highly variable effects postsynaptically, not restricted to perisomatic synapses and being more severe for the GABA_AR subunits and gephyrin than dystrophin. Altogether, the results confirm the importance of NL2 as organizer of the GABAergic PSD and unravel distinct roles for α1- and α2-GABA_ARs in the formation of GABAergic circuits in close interaction with the dystrophin-glycoprotein complex.

Keywords: Cholecystokinin; Dystrophin–glycoprotein complex; Gephyrin; Parvalbumin; Vesicular GABA transporter.