title: Hippocampal Endothelin-1 decreases excitability of pyramidal neurons and produces anxiolytic effects.
abstract: Anxiety disorders contribute to the pathophysiology of psychiatric diseases, including major depression, substance abuse, and schizophrenia. The hippocampus is important for anxiety modulation. However, the mechanisms that control the neuronal activity of the hippocampus in anxiety are still not clear. We found that Endothelin-1 (ET1) mRNA in the hippocampus was down-regulated in high-anxiety mice. Neutralizing endogenous ET1 in the hippocampal CA1 enhanced anxiety-like behaviors. We next revealed that most expression of ET1 and its receptors in the CA1 takes place in pyramidal neurons, and the ET1 signaling pathway directly regulated the excitability of CA1 pyramidal neurons and glutamatergic synaptic neurotransmission. Finally, we proved that neutralizing endogenous CA1 ET1 produces anxiogenic effects on low-anxiety mice, whereas infusing exogenous ET1 into the CA1 alleviates the anxiety susceptibility of high-anxiety mice. Together, these results indicate that ET1 signaling is critical in maintaining the excitability of glutamatergic neurons in the hippocampus and, thus, in modulating anxiety-like behaviors. Because ET1 is a risk factor for ischemic stroke, our findings might also help to explain the potential mechanism of emotional abnormality in stroke.
authors.affiliation: Department of Pathology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: The Institute for Brain Research (IBR), Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Shu
authors.affiliation: The Institute for Brain Research (IBR), Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Yan
authors.affiliation: The Institute for Brain Research (IBR), Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Pei
authors.affiliation: Department of Physiology, Basic Medical Sciences, Wuhan University School, Wuhan 430071, China.
authors.forename: Ze-Fen
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: Department of Physiology, Basic Medical Sciences, Wuhan University School, Wuhan 430071, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
authors.affiliation: Department of Pathology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Wuhan University Center for Pathology and Molecular Diagnostics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China. Electronic address: linlinbi2016@whu.edu.cn.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Bi
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000473:pathology*; D001703:Biophysics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects; D005508:Food Deprivation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D017466:Receptors, Endothelin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Anxiety; Endothelin1; Hippocampus; Neuron excitability