Department of Neurosciences, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
J Clin Invest. 2019 Jan 2;129(1):310-323. doi: 10.1172/JCI95731. Epub 2018 Dec 3.
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.
我们研究了新生海马齿状回颗粒细胞(DGCs)的病理变化如何导致癫痫。使用狂犬病毒介导的逆行追踪系统和 Designer Receptors Exclusively Activated by Designer Drugs(DREADD)化学遗传学方法,我们证明了新生海马 DGCs 是形成癫痫神经网络和诱导自发性反复性发作(SRS)所必需的。一项狂犬病毒介导的映射研究表明,海马新生 DGCs 的异常电路整合形成了过多的新兴奋性连接以及反复的兴奋性环路,使海马能够产生、放大和传播过多的反复性兴奋性信号。在癫痫小鼠中,DREADD 介导的海马新生 DGCs 的特异性抑制以可诱导和可逆的方式显著减少癫痫样棘波和 SRS。相反,海马新生 DGCs 的特异性激活增加了癫痫样棘波和 SRS。我们的研究揭示了海马新生 DGCs 在癫痫神经网络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。