REGIONAL AND SYNAPSE SUBTYPE-SPECIFIC FUNCTIONS OF NEUROLIGIN-2 AT GABAERGIC SYNAPSES IN THE MOUSE BRAIN

Dysfunction of inhibitory transmission disturbs the balance of excitation and inhibition (E/I), which contributes to neurological and psychiatric disorders. Despite its importance, the underlying mechanisms leading to E/I imbalance are poorly understood. GABA receptors of type A (GABAARs) are key regulators of neuronal activity and are recruited and anchored at GABAergic synapses by organizer complexes. The latter contain transsynaptic adhesion proteins such as Neuroligin-2 (Nlgn2). Nlgn2 variants have been shown to contribute to the pathophysiology of psychiatric disorders, and in mice, deletion of Nlgn2 impairs inhibitory synaptic transmission and leads to alterations in GABAAR clustering. However, it has been proposed that Nlgn2 may differentially affect synapses formed by different GABAergic neuron subclasses, albeit the precise nature and mechanisms of this differential function remain to be determined. Moreover, conflicting data exist for cortical vs. hippocampal regions, raising the intriguing possibility that there may be a regional specificity to the diversity of Nlgn2 function. To directly address these questions, this study aimed to compare the function of Nlgn2 at parvalbumin-, somatostatin- and vasoactive intestinal peptide-expressing GABAergic synapse subtypes in the medial prefrontal cortex and the hippocampal CA1 region, both of which have been associated with a variety of neurological and psychiatric disorders. To this end, an optogenetic approach was used to stimulate specific presynaptic neuron subtypes and simultaneously record postsynaptic responses from connected neurons. Our results confirm the notion that Nlgn2 function displays both regional and synapse subtype-specific diversity, providing important insights into how Nlgn2 shapes neuronal circuits in health and disease.