Mody Istvan
Departments of Neurology and Physiology, The David Geffen School of Medicine at UCLA, 635 Charles Young Dr S, Los Angeles, CA 90095
A variety of GABA receptor (GABAR) alterations have been described in human temporal lobe epilepsies (TLE) and in animal models of the disease. As tonically and phasically activated GABARs are distinct in their localization, physiological and pharmacological properties, and their function, it is important to distinguish between their alterations in TLE. This report summarizes our findings about the loss of δ-subunit containing GABARs (δ-GABARs) in granule cells of the dentate gyrus and its upregulation in molecular layer interneurons. In dentate gyrus granule cells, the tonic GABA conductance is mediated primarily by δ-GABARs and to a small extent by α5-subunit containing GABARs (α5-GABARs). Therefore, it was somewhat surprising to observe that following the loss of δ-GABARs from the dentate granule cells in the pilocarpine model of TLE in mice, the tonic GABA conductance was still present in these cells. However, pharmacological experiments with specific modulators of δ-GABARs have shown that the preserved tonic conductance is no longer mediated by δ-GABARs. In contrast to granule cells, inhibitory interneurons of the molecular layer had not lost their δ-GABARs, in fact it appeared that the levels of this subunit were upregulated in the latter neurons. Therefore, the tonic GABA conductance in these TLE-affected cells was also larger than that recorded in control molecular layer interneurons. Shifting the weight of δ-GABARs from principal cells to interneurons of the dentate gyrus in a mouse model of TLE implies that the dentate gate will have an entirely different pharmacological profile in TLE. Since δ-GABARs are quite sensitive to neurosteroids and ethanol, exposure of the dentate to these compounds in TLE will enhance excitability by dampening the function of interneurons and leaving the excitability of the granule cells untouched. The reduced interneuronal function in response to neurosteroids or ethanol in TLE may promote propagation of synchronous high frequency discharges through the dentate gyrus, and may lead to a further erosion of the dentate gate when these substances are present (e.g., stress, changes in the ovarian cycle, alcohol consumption).
在人类颞叶癫痫（TLE）及该疾病的动物模型中，已发现多种γ-氨基丁酸受体（GABAR）改变。由于持续性激活和相位性激活的GABAR在定位、生理和药理特性及其功能方面存在差异，因此区分它们在TLE中的改变非常重要。本报告总结了我们关于齿状回颗粒细胞中含δ亚基的GABAR（δ-GABAR）缺失及其在分子层中间神经元中上调的研究结果。在齿状回颗粒细胞中，持续性γ-氨基丁酸电导主要由δ-GABAR介导，在较小程度上由含α5亚基的GABAR（α5-GABAR）介导。因此，在小鼠TLE的毛果芸香碱模型中，观察到齿状颗粒细胞中δ-GABAR缺失后，这些细胞中仍存在持续性γ-氨基丁酸电导，这有点令人惊讶。然而，用δ-GABAR的特异性调节剂进行的药理学实验表明，保留的持续性电导不再由δ-GABAR介导。与颗粒细胞不同，分子层的抑制性中间神经元并未丢失其δ-GABAR，事实上，该亚基在后者神经元中的水平似乎上调了。因此，这些受TLE影响的细胞中的持续性γ-氨基丁酸电导也比对照分子层中间神经元中记录的电导大。在TLE小鼠模型中，将δ-GABAR的权重从主要细胞转移到齿状回的中间神经元意味着齿状门在TLE中将具有完全不同的药理学特征。由于δ-GABAR对神经甾体和乙醇相当敏感，在TLE中齿状回暴露于这些化合物将通过抑制中间神经元功能并使颗粒细胞的兴奋性保持不变来增强兴奋性。TLE中对神经甾体或乙醇反应的中间神经元功能降低可能促进同步高频放电通过齿状回的传播，并且当存在这些物质时（例如，压力、卵巢周期变化、饮酒）可能导致齿状门进一步受损。
