GABAB autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice
GABAB autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice
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DOI：
10.1073/pnas.1313505110
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发表时间：
2013-09-10
影响因子：
11.1
通讯作者：
Gloveli, Tengis
中科院分区：
文献类型：
--
作者：
Dugladze, Tamar;Maziashvili, Nino;Gloveli, Tengis
GABA（B）受体（GABA（B）Rs）介导对脑中神经元兴奋性和突触传递的缓慢抑制作用。然而，GABA（B）R激动剂巴氯芬也可以促进人类患者和动物模型中的兴奋性和癫痫发作。在这里，我们表明，巴氯芬具有浓度依赖性的影响，海马网络的内侧颞叶癫痫的小鼠模型。以高剂量（10 mg/kg i. p.）降低了自由活动癫痫小鼠的角氨区3（CA 3）区域中的γ振荡功率和病理性放电频率。出乎意料的是，在较低剂量（1 mg/kg）下，巴氯芬显著增加γ活性，伴有较高的病理性放电发生率。从体外CA 3锥体细胞的细胞内记录进一步表明，虽然在高浓度（10 μ M），巴氯芬总是导致超极化，在低浓度（0.5 μ M），药物有不同的效果，产生去极化和增加在癫痫，但不是控制小鼠的放电频率。这些兴奋作用是通过选择性抑制性胆囊收缩素阳性篮状细胞（CCK+ BCs）的突变介导的，通过增强突触前GABA（B）Rs对GABA释放的抑制。我们的结论是，细胞类型特异性上调GABA（B）R介导的CCK+ BCs的自抑制促进异常高频振荡和过度兴奋的慢性癫痫小鼠海马网络。
GABA(B) receptors (GABA(B)Rs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA(B)R agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of gamma oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased gamma activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 mu M), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 mu M), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK+ BCs), through enhanced inhibition of GABA release via presynaptic GABA(B)Rs. We conclude that cell type-specific up-regulation of GABA(B)R-mediated autoinhibition in CCK+ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.