Metaplastic Reinforcement of Long-Term Potentiation in Hippocampal Area CA2 by Cholinergic Receptor Activation

Abstract

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.

Alteration of hippocampal CA2 plasticity and social memory in adult rats impacted by juvenile stress

“…We have shown recently that cholinergic receptor activation induces an LTD of synaptic transmission at EC and SC‐CA2 synapses. This priming of synapses through neuromodulation by acetylcholine‐mediated LTD displays a bidirectional metaplastic switch to LTP on a futuristic timescale (Benoy et al, 2021 ). On that note, it will be worthwhile to explore whether SP mediated social memory after juvenile stress also emerges through similar mechanisms.…”

Machine learning-based segmentation of the rodent hippocampal CA2 area from Nissl-stained sections

“…Although we did not physiologically demonstrate that the RGS14-positive area in the vole hippocampus signified the CA2 area, performance of CAseg suggests that RGS14 can also be used as a marker protein for the vole CA2 area. Since the CA2 area has also been investigated in other rodent species such as rats ( Benoy et al, 2021 ), guinea pigs ( Bartesaghi and Severi, 2004 ), and gerbils ( Hisamatsu et al, 2016 ), a modified form of CAseg would precisely identify the rodent CA2 area in Nissl-stained brain sections. While the neurons of primates such as monkeys and humans also densely express RGS14 in a certain subarea of the hippocampus, which might represent the CA2 area ( Squires et al, 2018 ), extending capabilities of CAseg for such phylogenetically distant species is the future challenge.…”

Neuromodulator-dependent synaptic tagging and capture retroactively controls neural coding in spiking neural networks

“…Even without strong electrical stimulation, neuromodulators can induce a slow-onset potentiation that lasts for hours 49 , 70 , 79 , 80 . Furthermore, for different brain regions, there can be different neuromodulatory requirements for STC, for example in hippocampal CA1 vs. CA2 80 – 83 . Interestingly, synaptic as well as behavioral tagging also depend on sex and change with age and neurodegeneration 84 – 86 .…”