Direct Septum-Hippocampus Cholinergic Circuit Attenuates Seizure Through Driving Somatostatin Inhibition

Ying Wang; Yi Wang; Cenglin Xu; Shuang Wang; Na Tan; Cong Chen; Liying Chen; Xiaohua Wu; Fan Fei; Heming Cheng; Wenkai Lin; Yingbei Qi; Bin Chen; Jiao Liang; Junli Zhao; Zhenghao Xu; Yi Guo; Shihong Zhang; Xiaoming Li; Yudong Zhou; Shumin Duan; Zhong Chen

doi:10.1016/j.biopsych.2019.11.014

Direct Septum-Hippocampus Cholinergic Circuit Attenuates Seizure Through Driving Somatostatin Inhibition

Biol Psychiatry. 2020 May 1;87(9):843-856. doi: 10.1016/j.biopsych.2019.11.014. Epub 2019 Nov 26.

Authors

Ying Wang¹, Yi Wang², Cenglin Xu³, Shuang Wang⁴, Na Tan¹, Cong Chen⁴, Liying Chen¹, Xiaohua Wu⁴, Fan Fei¹, Heming Cheng¹, Wenkai Lin¹, Yingbei Qi¹, Bin Chen¹, Jiao Liang⁵, Junli Zhao¹, Zhenghao Xu¹, Yi Guo⁴, Shihong Zhang⁶, Xiaoming Li⁷, Yudong Zhou⁷, Shumin Duan⁷, Zhong Chen⁸

Affiliations

¹ Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
² Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Institute of Neuroscience, Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: wang-yi@zju.edu.cn.
³ Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Institute of Neuroscience, Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
⁴ Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁵ Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁶ Institute of Neuroscience, Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China.
⁷ Institute of Neuroscience, Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China; Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁸ Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Institute of Neuroscience, Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China; Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: chenzhong@zju.edu.cn.

PMID: 31987494
DOI: 10.1016/j.biopsych.2019.11.014

Abstract

Background: Previous studies indicated the involvement of cholinergic neurons in seizure; however, the specific role of the medial septum (MS)-hippocampus cholinergic circuit in temporal lobe epilepsy (TLE) has not yet been completely elucidated.

Methods: In the current study, we used magnetic resonance imaging and diffusion tensor imaging to characterize the pathological change of the MS-hippocampus circuit in 42 patients with TLE compared with 22 healthy volunteers. Using optogenetics and chemogenetics, combined with in vivo or in vitro electrophysiology and retrograde rabies virus tracing, we revealed a direct MS-hippocampus cholinergic circuit that potently attenuates seizure through driving somatostatin inhibition in animal TLE models.

Results: We found that patients with TLE with hippocampal sclerosis showed a decrease of neuronal fiber connectivity of the MS-hippocampus compared with healthy people. In the mouse TLE model, MS cholinergic neurons ceased firing during hippocampal seizures. Optogenetic and chemogenetic activation of MS cholinergic neurons (but not glutamatergic or GABAergic [gamma-aminobutyric acidergic] neurons) significantly attenuated hippocampal seizures, while specific inhibition promoted hippocampal seizures. Electrophysiology combined with modified rabies virus tracing studies showed that direct (but not indirect) MS-hippocampal cholinergic projections mediated the antiseizure effect by preferentially targeting hippocampal GABAergic neurons. Furthermore, chemogenetic inhibition of hippocampal somatostatin-positive (rather than parvalbumin-positive) subtype of GABAergic neurons reversed the antiseizure effect of the MS-hippocampus cholinergic circuit, which was mimicked by activating somatostatin-positive neurons.

Conclusions: These findings underscore the notable antiseizure role of the direct cholinergic MS-hippocampus circuit in TLE through driving the downstream somatostatin effector. This may provide a better understanding of the changes of the seizure circuit and the precise spatiotemporal control of epilepsy.

Keywords: Cholinergic neuron; Cholinergic receptor; Direct circuit; Epilepsy; Medial septum; Somatostatin inhibition.

Publication types

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

MeSH terms

Animals
Cholinergic Agents
Diffusion Tensor Imaging*
Hippocampus / metabolism
Humans
Mice
Seizures
Somatostatin* / metabolism

Substances

Cholinergic Agents
Somatostatin