UC Irvine

Long-term potentiation (LTP) shows memory-like consolidation and thus becomes increasingly stable over time. LTP quickly becomes resistant to disruption by non-LTD-inducing paradigms such as low frequency stimulation (LFS). However, it is known that nicotine application during LFS uniquely depotentiates consolidated LTP. Here, we investigated how nicotine allows LFS to disrupt stabilized LTP. We found that selective removal of hippocampal cholinergic inputs allowed for depotentiation of consolidated LTP in the absence of nicotine, implying that nicotine depotentiates consolidated LTP by preventing endogenous ACh signaling. Moreover, that 7 nicotinic acetylcholine receptor (nAChR) antagonists mimicked the effect of nicotine, indicating that nicotine's effect occurs through 7 nAChR desensitization. Furthermore, nicotine-induced depotentiation does not involve long-term depression mechanisms and requires the activation of GluN2A-containing NMDARs. We further examined whether nicotine-induced depotentiation involves the reversal of LTP mechanisms. Phosphorylation of Ser-831 on the GluA1 subunit of AMPARs increases single-channel conductance. LTP causes increased phosphorylation of Ser-831. This phosphorylation remained unchanged after nicotine-facilitated depotentiation. LTP involves the insertion of new AMPARs into the synapse; additionally, the internalization of AMPARs is associated with dephosphorylation of Ser-845 on GluA1 and caspase-3 activity. Nicotine-induced depotentiation occurred without dephosphorylation of the Ser-845 site and in the presence of a caspase-3 inhibitor. LTP is also accompanied by increased filamentous actin (F-actin) and spine enlargement. Nicotine-induced depotentiation was prevented by jasplakinolide, which stabilizes F-actin, suggesting that nicotine depotentiates consolidated LTP by destabilizing F-actin. Our results demonstrate a new role of nicotinic cholinergic system for protecting potentiated synapses from depotentiation via the interaction of 7 nAChR- and GluN2A-NMDAR-mediated signaling for modulating actin destabilization.