Hippocampal CA2 pyramidal cells project into both the neighboring CA1 and CA3 subfields, leaving them well positioned to influence network physiology and information processing for memory and space. While recent work has suggested unique roles for CA2, including encoding position during immobility and generating ripple oscillations, an interventional examination of the integrative functions of these connections has yet to be reported. Here we demonstrate that CA2 recruits feedforward inhibition in CA3 and that chronic genetically engineered shutdown of CA2-pyramidal-cell synaptic transmission consequently results in increased excitability of the recurrent CA3 network. In behaving mice, this led to spatially triggered episodes of network-wide hyperexcitability during exploration accompanied by the emergence of high-frequency discharges during rest. These findings reveal CA2 as a regulator of network processing in hippocampus and suggest that CA2-mediated inhibition in CA3 plays a key role in establishing the dynamic excitatory and inhibitory balance required for proper network function.

Hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels, which generate the I(h) current, mediate a number of important brain functions. The HCN1 isoform regulates dendritic integration in cortical pyramidal neurons and provides an inhibitory constraint on both working memory in prefrontal cortex and spatial learning and memory in the hippocampus. Altered expression of HCN1 following seizures may contribute to the development of temporal lobe epilepsy. Yet the regulatory networks and pathways governing HCN channel expression and function in the brain are largely unknown. Here, we report the presence of nine alternative N-terminal splice forms of the brain-specific cytoplasmic protein TRIP8b and demonstrate the differential effects of six isoforms to downregulate or upregulate HCN1 surface expression. Furthermore, we find that all TRIP8b isoforms inhibit channel opening by shifting activation to more negative potentials. TRIP8b thus functions as an auxiliary subunit that provides a mechanism for the dynamic regulation of HCN1 channel expression and function.

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.