Dentate granule cell GABAA receptors in epileptic hippocampus:: enhanced synaptic efficacy and altered pharmacology
Dentate granule cell GABAA receptors in epileptic hippocampus:: enhanced synaptic efficacy and altered pharmacology
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DOI：
10.1046/j.1460-9568.2003.02597.x
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发表时间：
2003-04-01
影响因子：
3.4
通讯作者：
Coulter, DA
中科院分区：
文献类型：
--
作者：
Cohen, AS;Lin, DD;Coulter, DA
齿状回（DG）通常起到过滤器的作用，阻止同步活动传播到易发生癫痫的海马体。DG的这种过滤器或“看门人”属性在各种病理状态下受到损害，包括颞叶癫痫（TLE）。本研究探讨的作用，改变抑制可能发挥恶化这一关键DG功能。使用毛果芸香碱动物模型的颞叶癫痫，我们表明，抑制性突触功能的DG的主细胞改变。癫痫动物齿状颗粒细胞（DGC）中记录的自发性微型抑制性突触后电流（mIPSC）较大，对锌的阻断更敏感，对苯二氮卓类药物位点1调节剂唑吡坦的增强不太敏感。此外，mIPSC在损伤后的静止期检查，但癫痫发作前显着小于那些存在于控制或TLE DGC，并已获得的敏感性，锌封锁自发性癫痫发作前。快速激动剂应用实验表明，需要长时间（>35 ms）暴露于锌，以阻断从癫痫DGC拉出的贴片中的GABA（A）受体（GABA（A）Rs）。因此，锌必须以张力存在以阻断DGC GABA（A）Rs并改变DG功能。这只会发生在苔藓纤维的重复激活过程中。因此，在TLE的毛果芸香碱动物模型中，锌敏感性GABA（A）Rs的早期从头表达与由含锌苔藓纤维复发性侧枝的异常发芽提供的锌递送系统的延迟癫痫诱导的发育相耦合。这些病理生理学改变的时间和空间并列可能会损害正常的“看门人”功能的DG通过动态锌诱导的抑制失败，诱发海马电路产生癫痫发作。
The dentate gyrus (DG) normally functions as a filter, preventing propagation of synchronized activity into the seizure-prone hippocampus. This filter or 'gatekeeper' attribute of the DG is compromised in various pathological states, including temporal lobe epilepsy (TLE). This study examines the role that altered inhibition may play in the deterioration of this crucial DG function. Using the pilocarpine animal model of TLE, we demonstrate that inhibitory synaptic function is altered in principal cells of the DG. Spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in dentate granule cells (DGCs) from epileptic animals were larger, more sensitive to blockade by zinc and less sensitive to augmentation by the benzodiazepine type site 1 modulator zolpidem. Furthermore, mIPSCs examined during a quiescent period following injury but preceding onset of epilepsy were significantly smaller than those present either in control or in TLE DGCs, and had already acquired sensitivity to blockade by zinc prior to the onset of spontaneous seizures. Rapid agonist application experiments demonstrated that prolonged (>35 ms) exposure to zinc is required to block GABA(A) receptors (GABA(A)Rs) in patches pulled from epileptic DGCs. Therefore, zinc must be tonically present to block DGC GABA(A)Rs and alter DG function. This would occur only during repetitive activation of mossy fibres. Thus, in the pilocarpine animal model of TLE, an early, de novo , expression of zinc-sensitive GABA(A)Rs is coupled with delayed, epilepsy-induced development of a zinc delivery system provided by aberrant sprouting of zinc-containing mossy fibre recurrent collaterals. The temporal and spatial juxtaposition of these pathophysiological alterations may compromise normal 'gatekeeper' function of the DG through dynamic zinc-induced failure of inhibition, predisposing the hippocampal circuit to generate seizures.