Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABA(A) receptors
Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABA(A) receptors
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DOI：
10.1523/jneurosci.17-19-07532.1997
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发表时间：
1997-10-01
影响因子：
5.3
通讯作者：
Macdonald, RL
中科院分区：
文献类型：
--
作者：
Kapur, J;Macdonald, RL
前脑快速突触抑制主要由GABA作用于GABA(A)受体介导。gabar受多种阳性（巴比妥类药物、苯二氮卓类药物和神经类固醇）和阴性（微毒素、双管碱和Zn2+）变构调节剂调节。在正常发育、慢性癫痫发展和长期暴露于GABAR激动剂后，GABAR对GABA和变构调节剂的敏感性逐渐改变。在这里，我们报道了在大鼠连续癫痫发作（癫痫持续状态）45分钟内发生的gabar快速功能可塑性的发展。在大鼠癫痫发作早期（癫痫发作10分钟后）给药时，用苯二氮卓类地西泮很容易终止癫痫发作。然而，在癫痫持续状态期间，地西泮终止癫痫发作的效力显著降低。为了确定动物对地西泮的敏感性丧失是否由GABAR功能特性的改变引起，我们从对照大鼠和处于癫痫持续状态的大鼠急性分离的海马齿状颗粒细胞中获得了全细胞GABAR电流。通过测定GABA敏感性和GABAR对苯二氮卓类药物、巴比妥类药物和Zn2+的敏感性来表征GABAR的性质。与对照组相比，处于癫痫持续状态的大鼠的GABAR电流对地西泮和Zn2+的敏感性降低，但对GABA和戊巴比妥的敏感性保持不变。我们得出结论，癫痫持续状态的长时间发作迅速改变了海马齿状颗粒细胞gabar的功能特性。
Fast synaptic inhibition in the forebrain is mediated primarily by GABA acting on GABA(A) receptors (GABARs). GABARs are regulated by numerous positive (barbiturates, benzodiazepines, and neurosteroids) and negative (picrotoxin, bicuculline, and Zn2+) allosteric modulators. The sensitivity of GABARs to GABA and to allosteric modulators changes gradually during normal development, during development of chronic epilepsy, and after prolonged exposure to GABAR agonists. Here we report the development of rapid functional plasticity of GABARs occurring over 45 min of continuous seizures (status epilepticus) in rats. Seizures induced in rats by administration of lithium followed by pilocarpine were readily terminated by the benzodiazepine diazepam when administered early during the seizures (after 10 min of seizures). However, during status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. To determine whether the loss of sensitivity of the animals to diazepam was caused by an alteration of GABAR functional properties, we obtained whole-cell GABAR currents from hippocampal dentate granule cells isolated acutely from control rats and from rats undergoing status epilepticus. GABAR properties were characterized by determining GABA sensitivity and the sensitivity of GABARs to regulation by benzodiazepines, barbiturates, and Zn2+. When compared with those from naive controls, GABAR currents from rats undergoing status epilepticus were less sensitive to diazepam and Zn2+ but retained their sensitivity to GABA and pentobarbital. We conclude that the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABARs.