Reducing premature KCC2 expression rescues seizure susceptibility and spine morphology in atypical febrile seizures
Reducing premature KCC2 expression rescues seizure susceptibility and spine morphology in atypical febrile seizures
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DOI：
10.1016/j.nbd.2016.02.014
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发表时间：
2016-07-01
影响因子：
6.1
通讯作者：
Di Cristo, Graziella
中科院分区：
文献类型：
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作者：
Awad, Patricia N.;Sanon, Nathalie T.;Di Cristo, Graziella
非典型热性惊厥被认为是日后癫痫发作和认知障碍的危险因素。颞叶癫痫患者和非典型热性癫痫发作史常携带皮质畸形。这种关联导致了一种假设，即皮质发育不良加剧了婴儿期的发热性癫痫发作，进而增加了神经系统后遗症的风险。目前，人们对这些事件之间的联系机制知之甚少。氯化钾共转运体KCC2通过调节gaba能传递和兴奋性突触的形成，影响神经元回路发育和功能的几个方面。最近的数据表明，KCC2下调有助于癫痫成人大脑的发作，但其在发育中的作用仍然存在争议。在非典型热性惊厥的啮齿动物模型中，结合皮质发育不良和高热诱发的惊厥（LHS大鼠），我们发现KCC2蛋白水平过早和持续增加，并伴有GABA逆转电位的负移。同时，我们观察到CA1锥体神经元的树突棘大小和mEPSC振幅显著减少，并伴有空间记忆缺陷。为了研究KCC2过早过表达是否在癫痫易感性和突触改变中起作用，我们通过在子宫内电穿孔shRNA选择性地降低了KCC2在海马锥体神经元中的表达。值得注意的是，KCC2 shrna电穿孔LHS大鼠表现出高温诱导的癫痫易感性降低，同时树突状脊柱大小缺陷得以恢复。我们的研究结果表明，KCC2在发育受损的大脑中过表达会增加热性癫痫发作的易感性，并导致树突状脊柱的改变。(C) 2016 Elsevier Inc .版权所有
Atypical febrile seizures are considered a risk factor for epilepsy onset and cognitive impairments later in life. Patients with temporal lobe epilepsy and a history of atypical febrile seizures often carry a cortical malformation. This association has led to the hypothesis that the presence of a cortical dysplasia exacerbates febrile seizures in infancy, in turn increasing the risk for neurological sequelae. The mechanisms linking these events are currently poorly understood. Potassium-chloride cotransporter KCC2 affects several aspects of neuronal circuit development and function, by modulating GABAergic transmission and excitatory synapse formation. Recent data suggest that KCC2 downregulation contributes to seizure generation in the epileptic adult brain, but its role in the developing brain is still controversial.In a rodent model of atypical febrile seizures, combining a cortical dysplasia and hyperthermia-induced seizures (LHS rats), we found a premature and sustained increase in KCC2 protein levels, accompanied by a negative shift of the reversal potential of GABA. In parallel, we observed a significant reduction in dendritic spine size and mEPSC amplitude in CA1 pyramidal neurons, accompanied by spatial memory deficits. To investigate whether KCC2 premature overexpression plays a role in seizure susceptibility and synaptic alterations, we reduced KCC2 expression selectively in hippocampal pyramidal neurons by in utero electroporation of shRNA. Remarkably, KCC2 shRNA-electroporated LHS rats show reduced hyperthermia-induced seizure susceptibility, while dendritic spine size deficits were rescued. Our findings demonstrate that KCC2 overexpression in a compromised developing brain increases febrile seizure susceptibility and contribute to dendritic spine alterations. (C) 2016 Elsevier Inc All rights reserved.