Augmentation of Endogenous Acetylcholine Uptake and Cholinergic Facilitation of Hippocampal Long-Term Potentiation by Acetylcholinesterase Inhibition

Takayoshi Masuoka; Junsuke Uwada; Makiko Kudo; Hatsumi Yoshiki; Yuka Yamashita; Takanobu Taniguchi; Matomo Nishio; Takaharu Ishibashi; Ikunobu Muramatsu

doi:10.1016/j.neuroscience.2019.01.042

Augmentation of Endogenous Acetylcholine Uptake and Cholinergic Facilitation of Hippocampal Long-Term Potentiation by Acetylcholinesterase Inhibition

Neuroscience. 2019 Apr 15:404:39-47. doi: 10.1016/j.neuroscience.2019.01.042. Epub 2019 Jan 30.

Authors

Takayoshi Masuoka¹, Junsuke Uwada², Makiko Kudo³, Hatsumi Yoshiki⁴, Yuka Yamashita³, Takanobu Taniguchi², Matomo Nishio³, Takaharu Ishibashi³, Ikunobu Muramatsu³

Affiliations

¹ Department of Pharmacology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan. Electronic address: masuoka@kanazawa-med.ac.jp.
² Division of Cellular Signal Transduction, Department of Biochemistry, Asahikawa Medical University, 2-1-1-1, Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
³ Department of Pharmacology, School of Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
⁴ Division of Genomic Science and Microbiology, School of Medicine, University of Fukui, Eiheiji, Fukui 910-1193, Japan.

PMID: 30708046
DOI: 10.1016/j.neuroscience.2019.01.042

Abstract

Hippocampal cholinergic activity enhances long-term potentiation (LTP) of synaptic transmission in intrahippocampal circuits and regulates cognitive function. We recently demonstrated intracellular distribution of functional M1-muscarinic acetylcholine receptors (mAChRs) and neuronal uptake of acetylcholine (ACh) in the central nervous system. Here we examined whether endogenous ACh acts on intracellular M1-mAChRs following its uptake and causes cholinergic facilitation of hippocampal LTP. ACh esterase (AChE) activities and [³H]ACh uptake was measured in rat hippocampal segments. LTP of evoked field excitatory postsynaptic potentials at CA1 synapses was induced by high frequency stimulation in hippocampal slices. Pretreatment with diisopropylfluorophosphate (DFP) irreversibly inhibited AChE, augmented ACh uptake, and significantly enhanced the LTP. This cholinergic facilitation was inhibited by pirenzepine, a membrane-permeable M1 antagonist, while only the early stage of cholinergic facilitation was inhibited by a membrane-impermeable M1 antagonist, muscarinic toxin 7. Tetraethylammonium (TEA) inhibited ACh uptake in hippocampal segments and selectively suppressed late stage cholinergic facilitation without changing the early stage. In contrast, LTP in DFP-untreated slices was not affected by the muscarinic antagonists and TEA. Carbachol (CCh; an AChE-resistant muscarinic agonist) competed with ACh for its uptake and produced cholinergic facilitation of LTP in DFP-untreated slices. The late stage of CCh-induced facilitation was also selectively inhibited by TEA. Our results suggest that when AChE is inactivated by inhibitors, LTP in hippocampal slices is significantly enhanced by endogenous ACh and that cholinergic facilitation is caused by direct activation of cell-surface M1-mAChRs and subsequent activation of intracellular M1-mAChRs after ACh uptake.

Keywords: acetylcholine; acetylcholine uptake; hippocampus; muscarinic receptor; synaptic plasticity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholine / metabolism*
Acetylcholinesterase / metabolism
Animals
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Hippocampus / drug effects
Hippocampus / metabolism*
Long-Term Potentiation / drug effects
Long-Term Potentiation / physiology*
Male
Organ Culture Techniques
Rats
Rats, Wistar
Receptors, Muscarinic / physiology*

Substances

Cholinesterase Inhibitors
Receptors, Muscarinic
Acetylcholinesterase
Acetylcholine