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 region has unique properties and connectivity. Notably, intra-hippocampal excitatory inputs to CA2 lack canonical 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. Furthermore, the sequentiality of DOR- and CB1R-mediated plasticity occurs in vivo during successive social interactions. 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. [Display omitted] •CB1R induces a long-term depression at inhibitory synapses in hippocampal area CA2•CB1R-LTD induction requires action potential firing in CA2 pyramidal neurons•CB1R-LTD is induced by social interactions and is required for social memory•CB1R-LTD is impaired in the 22q11.2 mouse model of schizophrenia Social recognition is important for gregarious animals. In this issue of Neuron, Loisy et al. describe a plasticity induced by CB1R that contributes to social memory formation. This plasticity is impaired in a mouse model of schizophrenia but is rescued by manipulation that rescues social memory in these mice.