Neuroligin1 in CCK-interneurons gates social memory formation via a disinhibitory microcircuit in the hippocampal CA2 in male mice

Social memory is essential for daily life, and its impairment is associated with psychiatric disorders. The dorsal CA2 (dCA2) region of the hippocampus is known to support social memory formation, yet how it processes social information remains unclear. Here we show that, in male mice, a specific group of dCA2 neurons—cholecystokinin-positive interneurons (CCK-INs)—acts as a hub that receives social cues and activates dCA2 pyramidal neurons (PyNs). Upon social encounters, CCK-INs are activated and suppress parvalbumin-positive interneurons (PV-INs) via GABAB receptors, thereby releasing PyNs from inhibition. The removal of Neuroligin 1, an autism-associated protein, from CCK-INs disrupts their function and leads to social memory deficits. Importantly, dCA2 CCK-INs receive direct glutamatergic inputs from the medial septum, and chemogenetic activation of these CCK-INs rescues memory deficits caused by septal inhibition. These findings delineate a important circuit mechanism for social memory and highlight potential therapeutic targets. In this study, the authors present that cholecystokinin-positive interneurons (CCK-INs) in hippocampal dorsal CA2 are essential for social memory encoding in male mice by mediating disinhibition of pyramidal neurons. Deficiency of Neuroligin 1 disrupts CCK-INs activity and induces social memory impairments, offering potential therapeutic targets for related psychiatric disorders.