Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures
Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures
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DOI：
10.1073/pnas.1810134115
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发表时间：
2018-10-02
影响因子：
11.1
通讯作者：
Moss, Stephen J.
中科院分区：
文献类型：
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作者：
Moore, Yvonne E.;Deeb, Tarek Z.;Moss, Stephen J.
2型K+/Cl-协同转运蛋白（KCC 2）允许神经元维持低的细胞内Cl-水平，这是有效突触抑制的先决条件。KCC 2活性的降低在癫痫中是明显的;然而，这些缺陷是否直接导致潜在的病理生理学仍然存在争议。为了解决这个问题，我们创建了敲入小鼠，其中KCC 2内的苏氨酸906和1007突变为丙氨酸（KCC 2-T906 A/T1007 A），这可以防止其磷酸依赖性失活。各小鼠表现正常，未显示任何明显的表型，基础神经元兴奋性不受影响。KCC 2-T906 A/T1007 A小鼠表现出基底神经元Cl-排出增加，而不改变KCC 2的总蓄积或质膜蓄积。重要的是，活动诱导的突触抑制缺陷在突变小鼠中减少。与此一致，增强KCC 2足以限制化学惊厥剂诱导的癫痫样活动。此外，KCC 2功能的增加减轻了癫痫发作期间异常高频活动的诱导，突出了去极化GABA作为癫痫中观察到的病理性神经元同步的关键因素。因此，我们的研究结果表明，增强KCC 2代表了缓解癫痫发作的治疗策略。
The type 2 K+/Cl- cotransporter (KCC2) allows neurons to maintain low intracellular levels of Cl-, a prerequisite for efficient synaptic inhibition. Reductions in KCC2 activity are evident in epilepsy; however, whether these deficits directly contribute to the underlying pathophysiology remains controversial. To address this issue, we created knock-in mice in which threonines 906 and 1007 within KCC2 have been mutated to alanines (KCC2-T906A/T1007A), which prevents its phospho-dependent inactivation. The respective mice appeared normal and did not show any overt phenotypes, and basal neuronal excitability was unaffected. KCC2-T906A/T1007A mice exhibited increased basal neuronal Cl- extrusion, without altering total or plasma membrane accumulation of KCC2. Critically, activity-induced deficits in synaptic inhibition were reduced in the mutant mice. Consistent with this, enhanced KCC2 was sufficient to limit chemoconvulsant-induced epileptiform activity. Furthermore, this increase in KCC2 function mitigated induction of aberrant high-frequency activity during seizures, highlighting depolarizing GABA as a key contributor to the pathological neuronal synchronization seen in epilepsy. Thus, our results demonstrate that potentiating KCC2 represents a therapeutic strategy to alleviate seizures.