Direct Septum-Hippocampus Cholinergic Circuit Attenuates Seizure Through Driving Somatostatin Inhibition
Direct Septum-Hippocampus Cholinergic Circuit Attenuates Seizure Through Driving Somatostatin Inhibition
复制标题
直接隔膜-海马胆碱能回路通过驱动生长抑素抑制来减轻癫痫发作
DOI：
10.1016/j.biopsych.2019.11.014
复制
发表时间：
2020-05-01
影响因子：
10.6
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
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作者：
Wang, Ying;Wang, Yi;Chen, Zhong
背景技术背景：以往的研究表明胆碱能神经元参与癫痫发作，然而内侧隔（MS）-海马胆碱能回路在颞叶癫痫（TLE）中的具体作用尚未完全阐明。在目前的研究中，我们使用磁共振成像和扩散张量成像来表征MS的病理变化-对42例TLE患者和22例健康志愿者的海马回路进行了比较。利用光遗传学和化学遗传学，结合在体内或体外电生理和逆行狂犬病毒示踪，我们揭示了一个直接MS-海马胆碱能电路，有力地减弱癫痫发作，通过驱动生长抑素抑制在动物TLE model.Results：我们发现，TLE患者海马硬化表现出减少的MS-海马神经纤维连接与健康人相比。在小鼠TLE模型中，MS胆碱能神经元在海马癫痫发作期间停止放电。MS胆碱能神经元的光遗传学和化学遗传学激活（但不是谷氨酸能或GABA能[γ-氨基丁酸能]神经元）显着减弱海马癫痫发作，而特异性抑制促进海马癫痫发作。电生理学结合狂犬病毒示踪研究表明，直接（而不是间接）MS-海马胆碱能投射介导的抗癫痫作用，优先针对海马GABA能神经元。此外，化学发生抑制海马生长抑素阳性（而不是小清蛋白阳性）亚型的GABA能神经元逆转MS-海马胆碱能电路，这是模仿激活生长抑素阳性neurons.CONCLUSIONS：这些研究结果强调显着的抗癫痫发作作用的直接胆碱能MS-海马电路在TLE通过驱动下游生长抑素效应。这将有助于更好地了解癫痫发作回路的变化和癫痫的精确时空控制。
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.