KCC2 is a vital neuronal K+/Cl- cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007 We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+ ) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology.

中文翻译：

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KCC2 磷酸化调节受损会导致神经元网络功能障碍和神经发育病理。


KCC2 是一种重要的神经元 K+/Cl- 协同转运蛋白，与许多神经系统疾病的病因有关。在正常细胞中，KCC2 在 Thr906 和 Thr1007 处经历发育性去磷酸化。我们对具有杂合磷酸模拟突变 T906E 和 T1007E (KCC2E/+) 的小鼠进行了改造，以防止这些位点的正常发育性去磷酸化。未成熟（出生后第 15 天）而非幼年（出生后第 30 天）KCC2E/+ 小鼠表现出 GABA 能抑制改变、谷氨酸/GABA 突触比率增加以及癫痫发作的敏感性更高。 KCC2E/+ 小鼠在出生后 10 至 12 天也出现异常超声发声，并在出生后第 60 天出现社交行为受损。出生后布美他尼治疗在出生后第 15 天恢复了网络活动，但在出生后第 60 天未能恢复社交行为。我们的数据表明，翻译后KCC2 调节控制体内 GABA 能发育序列，表明 KCC2 失调可能是神经病理学出现的危险因素。