Inhibitory plasticity permits the recruitment of CA2 pyramidal neurons by CA3

ABSTRACT

Area CA2 is emerging as an important region for hippocampal memory formation. However, how CA2 pyramidal neurons (PNs) are engaged by intra-hippocampal inputs remains unclear. Excitatory transmission between CA3 and CA2 is strongly inhibited and is not plastic. We show in mice that different patterns of activity can in fact increase the excitatory drive between CA3 and CA2. We provide evidence that this effect is mediated by a long-term depression at inhibitory synapses (iLTD), as it is evoked by the same protocols and shares the same pharmacology. In addition, we show that the net excitatory drive of distal inputs is also increased following iLTD induction. The dis-inhibitory increase in excitatory drive is sufficient to allow CA3 inputs to evoke action potential firing in CA2 PNs. Thus, these data reveal that the output of CA2 PNs can be gated by the unique activity-dependent plasticity of inhibitory neurons in area CA2.

Significance Statement: Long overlooked, recent work has demonstrated that area CA2 of the hippocampus is a critical region for social memory and aggression. How area CA2 integrates in the hippocampal circuit is not understood. While CA2 pyramidal neurons (PNs) receive excitatory input from CA3 PNs, these inputs cannot drive action potentials in CA2 PNs because of a large feed-forward inhibition. Furthermore, CA2 PNs do not express long-term potentiation, so it is unclear if CA2 PNs can be engaged by CA3. We demonstrate that a unique activity-dependent plasticity of CA2 interneurons can increase the excitatory/inhibitory balance between CA3 and CA2 PNs and allow the recruitment of CA2 PNs. Therefore, our results reveal a mechanism by witch CA2 PNs can be engaged by CA3.