Sequential inhibitory plasticities in hippocampal area CA2 and social memory formation

Area CA2 is a critical region for diverse hippocampal functions including social recognition memory. This re-gion has unique properties and connectivity. Notably, intra-hippocampal excitatory inputs to CA2 lack ca-nonical long-term plasticity, but inhibitory transmission expresses a long-term depression mediated by Delta-opioid receptors (DOR-iLTDs). Evidence indicates that DOR-iLTDs are insufficient to underlie social coding. Here, we report a novel inhibitory plasticity mediated by cannabinoid type 1 receptor activation (CB1R-iLTD). Surprisingly, CB1R-iLTD requires previous induction of DOR-iLTDs, indicating a permissive role for DOR plasticity. Blockade of CB1Rs in CA2 completely prevents social memory formation. Further-more, the sequentiality of DOR-and CB1R-mediated plasticity occurs in vivo during successive social inter-actions. Finally, CB1R-iLTD is altered in a mouse model of schizophrenia with impaired social cognition but is rescued by a manipulation that also rescues social memory. Altogether, our data reveal a unique interplay between two inhibitory plasticities and a novel mechanism for social memory formation.

Automated summary

This study reveals a novel inhibitory plasticity mediated by cannabinoid type 1 receptor activation (CB1R-iLTD) in the CA2 region of the hippocampus, which plays a crucial role in social memory formation. The study also demonstrates that the previous induction of Delta-opioid receptor-mediated long-term depression (DOR-iLTDs) is necessary for the CB1R-iLTD to occur. The findings provide insights into the interplay between inhibitory plasticities and a new mechanism for social memory formation.