Aberrant serotonergic signaling contributes to the hyperexcitability of CA1 pyramidal neurons in a mouse model of Alzheimer's disease

Jing Wang; Yufei Mei; Xiaoqin Zhang; Xiaojie Wei; Yiping Zhang; Dongpi Wang; Jinjin Huang; Keqing Zhu; Guoping Peng; Binggui Sun

doi:10.1016/j.celrep.2023.112152

Aberrant serotonergic signaling contributes to the hyperexcitability of CA1 pyramidal neurons in a mouse model of Alzheimer's disease

Cell Rep. 2023 Mar 28;42(3):112152. doi: 10.1016/j.celrep.2023.112152. Epub 2023 Feb 22.

Authors

Jing Wang¹, Yufei Mei², Xiaoqin Zhang³, Xiaojie Wei¹, Yiping Zhang¹, Dongpi Wang⁴, Jinjin Huang⁴, Keqing Zhu⁵, Guoping Peng⁶, Binggui Sun⁷

Affiliations

¹ Department of Neurobiology and Department of Anesthesiology, the Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
² Department of Neurobiology and Department of Anesthesiology, the Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; Brain Science and Advanced Technology Institute, School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430081, China. Electronic address: meiyufei1990@foxmail.com.
³ Department of Physiology and Pharmacology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, China.
⁴ Department of Anesthesiology, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310003, China.
⁵ National Human Brain Bank for Health and Disease and Department of Neurology in Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
⁶ Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China. Electronic address: guopingpeng@zju.edu.cn.
⁷ Department of Neurobiology and Department of Anesthesiology, the Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310058, China; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: bsun@zju.edu.cn.

PMID: 36821438
DOI: 10.1016/j.celrep.2023.112152

Abstract

Hyperactivity of pyramidal neurons (PNs) in CA1 is an early event in Alzheimer's disease. However, factors accounting for the hyperactivity of CA1 PNs remain to be completely investigated. In the present study, we report that the serotonergic signaling is abnormal in the hippocampus of hAPP-J20 mice. Interestingly, chemogenetic activation of serotonin (5-hydroxytryptamine; 5-HT) neurons in the median raphe nucleus (MRN) attenuates the activity of CA1 PNs in hAPP-J20 mice by regulating the intrinsic properties or inhibitory synaptic transmission of CA1 PNs through 5-HT3aR and/or 5-HT1aR. Furthermore, activating MRN 5-HT neurons improves memory in hAPP-J20 mice, and this effect is mediated by 5-HT3aR and 5-HT1aR. Direct activation of 5-HT3aR and 5-HT1aR with their selective agonists also improves the memory of hAPP-J20 mice. Together, we identify the impaired 5-HT/5-HT3aR and/or 5-HT/5-HT1aR signaling as pathways contributing to the hyperexcitability of CA1 PNs and the impaired cognition in hAPP-J20 mice.

Keywords: Alzheimer’s disease; CA1 pyramidal neurons; CP: Neuroscience; amyloid-β; chemogenetics; electrophysiology; fiber photometry; hyperactivity; median raphe nucleus; memory; serotonin.

Publication types

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

MeSH terms

Alzheimer Disease* / metabolism
Animals
Hippocampus / metabolism
Mice
Mice, Transgenic
Neurons / metabolism
Pyramidal Cells / metabolism
Serotonin / metabolism

Substances

Serotonin