Hippocampal CA2 to CA1: A metaplastic switch for memory encoding

The hippocampus is essential for spatial and episodic memory, subserved by CA1 neurons. Hippocampal area CA2, which processes social memory, also makes direct connections to CA1. However, the function of these connections is unknown. To test whether CA2-CA1 connections might facilitate the interaction of social and episodic memories, we used models of behaving mice and in vitro electrophysiology that allow prior activation of CA2 by either novel social interaction or electrical stimulation before inhibitory avoidance training or induction of activity-dependent synaptic plasticity in CA1. We show that social novelty promotes consolidation of CA1-associated memory, which was blocked by the selective chemogenetic silencing of CA1-projecting CA2 neurons. In both cases, CA2 priming was time-dependent, involved direct CA2-CA1 connections, increased expression of plasticity protein protein kinase M zeta (PKMζ), and promoted associativity via synaptic tagging and capture. Taken together, CA2-CA1 connections can significantly impact CA1 plasticity and memory consolidation. The inclusion of CA2 into hippocampal circuitry and function broadens the role of the hippocampus as an integrative memory hub.