KCC2 is required for the survival of mature neurons but not for their development.
KCC2 is required for the survival of mature neurons but not for their development.
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DOI：
10.1016/j.jbc.2021.100364
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Smalley JL
中科院分区：
文献类型：
--
作者：
Kontou G;Josephine Ng SF;Cardarelli RA;Howden JH;Choi C;Ren Q;Rodriguez Santos MA;Bope CE;Dengler JS;Kelley MR;Davies PA;Kittler JT;Brandon NJ;Moss SJ;Smalley JL
K+/Cl−协同转运蛋白KCC 2（SLC 12 A5）允许CNS中的成熟神经元维持低细胞内Cl−水平，这对于通过A型γ-氨基丁酸受体（GABAAR）介导快速超极化突触抑制至关重要。根据这一点，受损的KCC 2活性导致癫痫发作，但这种缺陷是否直接导致神经元结构和活力的后续变化，导致癫痫发生仍有待评估。典型的超极化GABAAR电流在出生后发展，这反映了KCC 2表达水平和活性的进行性增加。为了研究KCC 2在调节神经元活力和结构中的作用，我们有条件地消融了发育和成熟神经元中的KCC 2表达。成熟神经元中KCC 2表达的降低导致外源性凋亡途径的快速激活。有趣的是，在成熟神经元中直接药理学抑制KCC 2足以快速诱导细胞凋亡，通过使用河豚毒素（TTX）阻断神经元去极化，这种作用不会被消除。与此相反，消融KCC 2表达在未成熟的神经元没有明显的影响，其随后的发展，树枝状，或树突状结构。然而，在未成熟的神经元中去除KCC 2足以消融随后的出生后超极化GABAAR电流的发展。总的来说，我们的研究结果表明，KCC 2通过限制细胞凋亡在神经元存活中起着关键作用，成熟神经元对KCC 2功能的丧失高度敏感。相比之下，KCC 2似乎在介导神经元发育或结构中发挥最小的作用。
The K+/Cl− cotransporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl− levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A γ-aminobutyric acid receptors (GABAARs). In accordance with this, compromised KCC2 activity results in seizures, but whether such deficits directly contribute to the subsequent changes in neuronal structure and viability that lead to epileptogenesis remains to be assessed. Canonical hyperpolarizing GABAAR currents develop postnatally, which reflect a progressive increase in KCC2 expression levels and activity. To investigate the role that KCC2 plays in regulating neuronal viability and architecture, we have conditionally ablated KCC2 expression in developing and mature neurons. Decreasing KCC2 expression in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons was sufficient to rapidly induce apoptosis, an effect that was not abrogated via blockade of neuronal depolarization using tetrodotoxin (TTX). In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization, or dendritic structure. However, removing KCC2 in immature neurons was sufficient to ablate the subsequent postnatal development of hyperpolarizing GABAAR currents. Collectively, our results demonstrate that KCC2 plays a critical role in neuronal survival by limiting apoptosis, and mature neurons are highly sensitive to the loss of KCC2 function. In contrast, KCC2 appears to play a minimal role in mediating neuronal development or architecture.
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影响因子：
4.2
作者：
Pineda, Jose A.;Lewis, Stephen B.;Hayes, Ronald L.
通讯作者：
Hayes, Ronald L.
DOI：
10.1073/pnas.1810134115
发表时间：
2018-10-02
影响因子：
11.1
作者：
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Moss, Stephen J.
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Frahm, Christiane
影响因子：
3.7
作者：
Fiumelli, Hubert;Briner, Adrian;Vutskits, Laszlo
通讯作者：
Vutskits, Laszlo
影响因子：
7.3
作者：
Friedel, Perrine;Kahle, Kristopher T.;Medina, Igor
通讯作者：
Medina, Igor