Exploring the Mechanisms of Associative Plasticity within and between Hippocampal Areas CA1 and CA2

The hippocampus plays an integral role in episodic memory, primarily through neurons in the CA1 subfield. Beyond the well-established canonical circuitry, the CA2 region is implicated in social memory. CA2 neurons also display unique biochemical properties and are more resistant to plasticity. Our earlier studies observed metaplastic effects of neuromodulators that permit plasticity in CA2 neurons. Notably, there are monosynaptic connections from CA2 that innervate CA1, the functional relevance of which remains relatively unknown. Our study aims to investigate how these CA2-CA1 connections can modulate the maintenance of functional plasticity models, such as long-term potentiation (LTP) and long-term depression (LTD), within the Schaffer collateral (SC)-CA1 synapses. Subthreshold stimulation of SC-CA1 synapses revealed an early form of LTP (early-LTP) but not the persistent late form (late-LTP). However, when ‘primed’ by the activation of CA2, SC-CA1 synapses exhibit protein synthesis-dependent late-LTP upon subthreshold stimulation within a temporal window that also promotes associative plasticity, such as synaptic tagging and capture (STC). Moreover, CA2 ‘priming’ does not disrupt the persistence of late forms of LTD when SC-CA1 synapses are stimulated by strong low-frequency stimulation. In fact, weak low-frequency stimulation can promote protein synthesis-dependent late-LTD in CA2-primed SC-CA1 synapses. Lastly, we established a behavioral model wherein social novelty, which activates CA2, can enhance the persistence of CA1-dependent memory via the weak inhibitory avoidance task. Combining a chemogenetics approach with behavioral assays also confirmed the role of CA2 in enhancing CA1-dependent memory. This set of results demonstrates that CA2 connections onto CA1 can influence the synaptic plasticity of CA1, suggesting possible implications for how social behavioral states can modulate the persistence of memory.