Contribution of K+–Cl− cotransporter 2 in MK-801-induced impairment of long term potentiation
Contribution of K+–Cl− cotransporter 2 in MK-801-induced impairment of long term potentiation
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K-Cl-协同转运蛋白 2 在 MK-801 诱导的长时程增强损伤中的作用
DOI：
10.1016/j.bbr.2009.02.028
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发表时间：
2009-08
影响因子：
2.7
通讯作者：
刘勇
中科院分区：
文献类型：
--
作者：
刘勇
以往的研究表明，GABA能去抑制参与了由NMDA受体功能低下所介导的大鼠精神分裂症模型的认知功能障碍。然而，精神分裂症患者GABA能去抑制的潜在机制仍然不清楚。在本研究中，我们发现在MK-801诱导的认知障碍大鼠的海马区，长时程增强(LTP)的维持受到损害。GABA受体-氯通道阻断剂苦参碱和K+-氯−协同转运体2(KCC2)阻断剂速尿均能显著逆转上述作用。免疫印迹结果显示，在LTP诱导前，MK-801处理组大鼠海马CA1区KCC2的表达低于正常大鼠。此外，MK-801处理的大鼠在LTP诱导过程中，LTP伴随的KCC2表达下调也被阻止。结果提示，LTP诱导MK-801处理的大鼠海马CA1区KCC2的表达降低，但并未进一步降低其表达。因此，在LTP诱导过程中，由于MK-801处理的大鼠基础GABA能张力降低，GABA能抑制没有进一步减少，因此，在MK-801处理的大鼠中，GABA能去抑制限制了LTP诱导过程中KCC2的进一步下调，并有助于稳定的GABA能抑制和LTP表达受损。因此，我们的结果揭示了GABA能去抑制导致认知缺陷的机制。
Previous studies have indicated that GABAergic disinhibition contributes to cognitive deficits mediated by NMDA receptor hypofunction in schizophrenia model of rats. However, the underlying mechanism of GABAergic disinhibition in schizophrenia remains elusive. In this study, we found that the maintenance of long term potentiation (LTP) was impaired in the hippocampus of rats with MK-801-induced cognitive impairments. The impairment of LTP maintenance was significantly reversed by picrotoxinin, a specific GABAAreceptor-chloride channel blocker and furosemide, a K+–Cl−cotransporter 2 (KCC2) blocker, respectively. Furthermore, immunoblotting results indicated KCC2 expression in hippocampal CA1 of MK-801-treated rats was lower than that of normal rats before LTP induction. Additionally, LTP-accompanied downregulation of KCC2 was prevented in MK-801-treated rats during LTP induction. Our results suggested that KCC2 expression in hippocampal CA1 of MK-801-treated rats was not further decreased by LTP induction because of its low expression caused by MK-801 treatment. Accordingly, GABAergic inhibition was not further decreased during LTP induction due to the depressed basal GABAergic tone in MK-801-treated rats, Therefore, GABAergic disinhibition in MK-801-treated rats restricts the further downregulation of KCC2 during LTP induction and contributes to the stable GABAergic inhibition and the impaired LTP expression. Our results thus reveal the mechanism that GABAergic disinhibition contributes to cognitive deficits.
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影响因子：
2.9
作者：
G. Burgos;F. I. Biali;D. Cardinali
通讯作者：
G. Burgos;F. I. Biali;D. Cardinali
DOI：
10.1016/j.bbrc.2006.03.038
发表时间：
2006-05
影响因子：
3.1
作者：
Wei Wang;Neng Gong;Tian-Le Xu
通讯作者：
Wei Wang;Neng Gong;Tian-Le Xu
影响因子：
5.5
作者：
Rivera, C;Voipio, J;Kaila, K
通讯作者：
Kaila, K
影响因子：
2.9
作者：
GORTER, JA;DEBRUIN, JPC
通讯作者：
DEBRUIN, JPC
影响因子：
5.3
作者：
Pathak, Hemal R.;Weissinger, Florian;Coulter, Douglas A.
通讯作者：
Coulter, Douglas A.