Sustained depolarizing shift of the GABA reversal potential by glutamate receptor activation in hippocampal neurons
Sustained depolarizing shift of the GABA reversal potential by glutamate receptor activation in hippocampal neurons
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DOI：
10.1016/j.neures.2008.09.002
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发表时间：
2008-12-01
影响因子：
2.9
通讯作者：
Nabekura, Junichi
中科院分区：
文献类型：
--
作者：
Kitamura, Akihiko;Ishibashi, Hitoshi;Nabekura, Junichi
GABA的抑制作用是相对超极化的Cl-逆转电位（E-Cl）的结果，这是由K+-Cl-共转运体（KCC 2）的活性引起的。在这项研究中，我们研究了谷氨酸和谷氨酸能突触活动对E-Cl的影响。在分离培养的成熟海马神经元中，谷氨酸的应用引起了两个不同的时间成分的正E-Cl移位。在一个大的短暂去极化状态，持续去极化状态（E-Cl-持续）持续超过30分钟。E-Cl-持续消失在外部钙离子的情况下，在谷氨酸盐的应用程序，并被阻止AP 5和MK 801，但不是硝苯地平。NMDA也可诱导E-Cl-持续。E-Cl-持续被KCC 2和NKCC 1的阻断剂呋塞米阻断，但不是NKCC 1的阻断剂布美他尼。另一方面，在KCC 2表达较少的未成熟神经元中，NMDA未能诱导持续的去极化E-Cl移位。在器官型切片培养的神经元中，重复激活多巴胺能传入也产生持续的去极化E-Cl移位。这些结果表明，通过NMDA受体的Ca ~（2+）内流引起KCC_2的下调，并引起持久的正E-Cl位移，这可能有助于过度兴奋，LTP和癫痫样放电。(C)2008年爱思唯尔爱尔兰有限公司和日本神经科学学会。All rights reserved.
The inhibitory action of GABA is a consequence of a relatively hyperpolarized Cl- reversal potential (E-Cl), which results from the activity of K+-Cl- cotransporter (KCC2). In this study we investigated the effects of glutamate and glutamatergic synaptic activity on E-Cl. In dissociated culture of mature hippocampal neurons, the application of glutamate caused positive E-Cl shifts with two distinct temporal components. Following a large transient depolarizing state, the sustained depolarizing state (E-Cl-sustained) lasted more than 30 min. The E-Cl-sustained disappeared in the absence of external Ca2+ during glutamate application and was blocked by both AP5 and MK801, but not by nifedipine. The E-Cl-sustained was also induced by NMDA. The E-Cl-sustained was blocked by furosemide, a blocker of both KCC2 and NKCC1, but not bumetanide, a blocker of NKCC1. On the other hand, in immature neurons having less expression of KCC2, NMDA failed to induce the sustained depolarizing E-Cl shift. In organotypic slice cultured neurons, repetitive activation of glutamatergic afferents also generated a sustained depolarizing E-Cl shift. These results suggest that Ca2+ influx through NMDA receptors causes the down-regulation of KCC2 and gives rise to long lasting positive E-Cl shifts, which might contribute to hyperexcitability, LTP, and epileptiform discharges. (C) 2008 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.