Reduction of acetylcholine in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice

Yuko Kondo-Takuma,Yuta Madokoro,Hiroshi Takase,Masayuki Mizuno,Hideki Hida,Noriyuki Matsukawa,Yuto Uchida,Cesario V Borlongan,Yo Tsuda,Toyohiro Sato,Ken-Ichi Adachi,Kengo Suzuki

doi:10.1038/s41598-021-01667-8

Yuko Kondo-Takuma, Yuta Madokoro + Show 10 more

Open Access

https://doi.org/10.1038/s41598-021-01667-8

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Abstract

The cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine (Ach) synthesis in the medial septal nuclei of an explant culture system, was purified from the soluble fraction of postnatal rat hippocampus. HCNP is processed from the N-terminal region of a 186-amino acid, 21-kDa HCNP precursor protein, also known as Raf kinase inhibitory protein and phosphatidylethanolamine-binding protein 1. Here, we confirmed direct reduction of Ach release in the hippocampus of freely moving HCNP-pp knockout mice under an arousal state by the microdialysis method. The levels of vesicular acetylcholine transporter were also decreased in the hippocampus of these mice in comparison with those in control mice, suggesting there was decreased incorporation of Ach into the synaptic vesicle. These results potently indicate that HCNP may be a cholinergic regulator in the septo-hippocampal network.

Highlights

The cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes
We demonstrated that the Ach release into the extracellular space in the ventral hippocampus of Hippocampal cholinergic neurostimulating peptide (HCNP)-pp KO mice was significantly lower than that in control mice using the in vivo microdialysis method
The vesicular acetylcholine transporter (VAchT) levels decreased in the hippocampus of HCNP precursor protein (HCNP-pp) KO mice in comparison with those in the control mice, suggesting that Ach secretion is inhibited at cholinergic terminals

Summary

Introduction

The cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes This cholinergic projection can generate theta oscillations in the hippocampus to encode novel information. The levels of vesicular acetylcholine transporter were decreased in the hippocampus of these mice in comparison with those in control mice, suggesting there was decreased incorporation of Ach into the synaptic vesicle These results potently indicate that HCNP may be a cholinergic regulator in the septo-hippocampal network. Abbreviations HCNP Hippocampal cholinergic neurostimulating peptide HCNP-pp Hippocampal cholinergic neurostimulating peptide precursor protein Ach Acetylcholine ChAT Cholineacetyltransferase VAchT Vesicular acetylcholine transporter RKIP Raf kinase inhibitory protein PEBP1 Phosphatidylethanolamine-binding protein 1 MSN Medial septal nucleus. Whereas no significant difference in number of ChAT positive neurons in the MSN was shown, the vesicular acetylcholine transporter (VAchT) levels in the hippocampus of those mice were lower than those in the littermate control mice (Control), suggesting decreased incorporation of Ach into synaptic vesicles

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Conclusion