期刊
JOURNAL OF NEUROSCIENCE
卷 41, 期 44, 页码 9082-9098出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2885-20.2021
关键词
acetylcholine; hippocampal CA2; LTD; LTP; metaplasticity; cholinergic receptors
资金
- National Medical Research Council [NMRC-CBRG-0099-2015, NMRC/OFIRG/0037/2017]
- Ministry of Education [MOE2017-T3-1-002]
- NUSMed-FoS Joint Research Program [NUHSRO/2018/075/NUSMed-FoS/01]
- NUS
- Natural Science Foundation of China [31871076]
- Shanghai Municipal Science and Technology Major Project [2018SHZDZX01]
- ZJLab
- Shanghai Center for Brain Science and Brain-Inspired Technology
Research shows that activation of cholinergic receptors in the hippocampal CA2 area regulates synaptic plasticity, with muscarinic acetylcholine receptors playing a role in early facilitation and nicotinic acetylcholine receptors involved in late maintenance. Furthermore, priming with cholinergic stimulation lowers the threshold for subsequent long-term potentiation induction and demonstrates a metaplastic regulation of CA2 synaptic learning rules.
Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years because of its role in social memory formation. However, the role of cholinergic inputs to the CA2 area for the regulation of synaptic plasticity remains to be fully understood. We show that cholinergic receptor activation with the nonselective cholinergic agonist, carbachol (CCh), triggers a protein synthesis-dependent and NMDAR-independent long-term synaptic depression (CCh-LTD) at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses in the hippocampus of adult male Wistar rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of CCh-LTD with the results suggesting an involvement of M3 and M1 mAChRs in the early facilitation of CCh-LTD, while nicotinic AChR activation plays a role in the late maintenance of CCh-LTD at CA2 synapses. Remarkably, we find that CCh priming lowers the threshold for the subsequent induction of persistent long-term potentiation (LTP) of synaptic transmission at EC-CA2 and the plasticity-resistant SC-CA2 pathways. The effects of such a cholinergic-dependent synaptic depression on subsequent LTP at EC-CA2 and SC-CA2 synapses have not been previously explored. Collectively, the results demonstrate that CA2 synaptic learning rules are regulated in a metaplastic manner, whereby modifications triggered by prior cholinergic stimulation can dictate the outcome of future plasticity events. Moreover, the reinforcement of LTP at EC inputs to CA2 following the priming stimulus coexists with concurrent sustained CCh-LTD at the SC-CA2 pathway and is dynamically scaled by modulation of SC-CA2 synaptic transmission.
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