Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits
Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits
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海马神经元的化学遗传学沉默抑制癫痫神经回路
DOI：
10.1172/jci95731
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发表时间：
2019-01-02
影响因子：
15.9
通讯作者：
Suh, Hoonkyo
中科院分区：
文献类型：
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作者：
Zhou, Qi-Gang;Nemes, Ashley D.;Suh, Hoonkyo
我们研究了新生儿海马齿状颗粒细胞（DGCs）的病理改变如何导致癫痫。利用狂犬病毒介导的逆行追踪系统和专门由设计药物激活的设计受体（DREADD）化学发生方法，我们证明了新生儿海马DGCs是癫痫神经回路形成和诱导自发性复发性癫痫（SRS）所必需的。一项狂犬病毒介导的图谱研究表明，海马新生DGCs的异常电路整合形成了过多的新生兴奋性连接和反复兴奋性回路，使海马产生、放大和传播过多的反复兴奋性信号。在癫痫小鼠中，fdd介导的海马新生DGCs特异性抑制以诱导和可逆的方式显著降低了癫痫尖峰和SRS。相反，海马新生DGCs的特异性激活增加了癫痫峰和SRS。我们的研究揭示了海马新生DGCs在癫痫神经回路的形成和功能中的重要作用，为DGCs作为治疗癫痫的潜在治疗靶点提供了重要的见解。
We investigated how pathological changes in newborn hippocampal dentate granule cells (DGCs) lead to epilepsy. Using a rabies virus-mediated retrograde tracing system and a designer receptors exclusively activated by designer drugs (DREADD) chemogenetic method, we demonstrated that newborn hippocampal DGCs are required for the formation of epileptic neural circuits and the induction of spontaneous recurrent seizures (SRS). A rabies virus-mediated mapping study revealed that aberrant circuit integration of hippocampal newborn DGCs formed excessive de novo excitatory connections as well as recurrent excitatory loops, allowing the hippocampus to produce, amplify, and propagate excessive recurrent excitatory signals. In epileptic mice, DREADD-mediated-specific suppression of hippocampal newborn DGCs dramatically reduced epileptic spikes and SRS in an inducible and reversible manner. Conversely, specific activation of hippocampal newborn DGCs increased both epileptic spikes and SRS. Our study reveals an essential role for hippocampal newborn DGCs in the formation and function of epileptic neural circuits, providing critical insights into DGCs as a potential therapeutic target for treating epilepsy.