Metaplastic reinforcement of long-term potentiation in rat hippocampal area CA2 by cholinergic receptor activation

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years due to its role in the formation of social memory. The effects of synaptic depression for subsequent long-term potentiation (LTP) of synaptic transmission at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses have not been previously explored. Here we show that cholinergic receptor activation with the non-selective cholinergic agonist carbachol (CCh) triggers a long-term synaptic depression (CCh-LTD) of field excitatory postsynaptic potentials at EC- and SC-CA2 synapses in the hippocampus of adult rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of an early phase ( 100 min) of CCh-LTD. Importantly, CCh priming lowers the threshold, in a protein synthesis-dependent manner, for the late maintenance of LTP that can be subsequently induced by high-frequency electrical stimulation at EC- or SC-CA2 pathways. The results demonstrate that CA2 synaptic learning rules are modified in a metaplastic manner, wherein synaptic modifications triggered by cholinergic stimulation can dictate the outcome of future plasticity events. Moreover, the observed enabling of late LTP at EC inputs to CA2 following the priming stimulus co-exists with concurrent sustained CCh-LTD at SC-CA2 and is dynamically scaled by modulation of SC-CA2 synaptic transmission.