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
Affiliations
Jing Wang
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
Yufei Mei
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; Corresponding author
Xiaoqin Zhang
Department of Physiology and Pharmacology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, China
Xiaojie Wei
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
Yiping Zhang
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
Dongpi Wang
Department of Anesthesiology, The Children’s Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310003, China
Jinjin Huang
Department of Anesthesiology, The Children’s Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310003, China
Keqing Zhu
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
Guoping Peng
Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Corresponding author
Binggui Sun
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; Corresponding author
Summary: 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.
