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

神经科学 海马体 胆碱能的 海马结构 胆碱能神经元 光遗传学 加巴能 化学 生物 抑制性突触后电位
作者
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,Shi‐Hong Zhang,Xiao‐Ming Li,Yu‐Dong Zhou,Shumin Duan,Zhong Chen
出处
期刊:Biological Psychiatry [Elsevier]
卷期号:87 (9): 843-856 被引量:68
标识
DOI:10.1016/j.biopsych.2019.11.014
摘要

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.
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