Contribution of intracellular acetylcholine receptor to hippocampal long-term potentiation

[Speaker] Takayoshi Masuoka:1
[Co-author] Makiko Kudo:1, Matomo Nishio:1, Ikunobu Muramatsu:1, Takaharu Ishibashi:1
1:Department of Pharmacology, School of Medicine, Kanazawa Medical University, Japan

Activation of muscarinic acetylcholine receptors M1 (M1-mAChRs) is known to facilitate the induction of long-term potentiation (LTP) in hippocampal CA1. We previously reported that M1-mAChRs are functionally expressed in the intracellular membranes, such as endoplasmic reticulum and Golgi apparatus, as well as cell-surface, in neuroblastoma cells and neurons in central nervous system. In this study, we took the extracellular field recording in acute hippocampal slice preparation to examine how cell-surface and intracellular M1-mAChRs regulates hippocampal LTP.
LTP in hippocampal CA1was observed 60 min after high frequency stimulation (HFS) at Schaffer collaterals. Pretreatment with carbachol (CCh) significantly enhanced LTP beyond 1h after HFS, and the facilitation was thoroughly inhibited by pirenzepine, a cell-permeable M1 antagonist. On the other hand, a cell-impermeable M1 antagonist, MT7, inhibited the early part of facilitation (5-15 min) without affecting the late part (50-60 min). Tetraethylammonium (TEA), an acetylcholine uptake inhibitor, also selectively suppressed the late part of facilitation. Next, we examined the effect of diisopropyl fluorophosphate (DFP), an irreversible cholinesterase inhibitor thereupon. Pretreatment with DFP also significantly and persistently enhanced LTP after HFS, and the facilitation was also completely inhibited by pirenzepine. In addition, MT7 selectively suppressed the early part of facilitation, while TEA attenuated the late part of facilitation.
These results suggest that an exogenous cholinergic agonist or endogenously released acetylcholine acts on both the cell-surface and the intracellular M1-mAChRs, resulting in augment of hippocampal LTP.

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