Eichler Sabrina A, Kirischuk Sergei, Jüttner René, Schaefermeier Philipp K, Legendre Pascal, Lehmann Thomas-Nicolas, Gloveli Tengis, Grantyn Rosemarie, Meier Jochen C
RNA Editing and Hyperexcitability Disorders Helmholtz Group, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
J Cell Mol Med. 2008 Dec;12(6B):2848-66. doi: 10.1111/j.1582-4934.2008.00357.x.
An increasing number of epilepsy patients are afflicted with drug-resistant temporal lobe epilepsy (TLE) and require alternative therapeutic approaches. High-affinity glycine receptors (haGlyRs) are functionally adapted to tonic inhibition due to their response to hippocampal ambient glycine, and their synthesis is activity-dependent. Therefore, in our study, we scanned TLE hippocampectomies for expression of haGlyRs and characterized the effects mediated by these receptors using primary hippocampal neurons. Increased haGlyR expression occurred in TLE hippocampi obtained from patients with a severe course of disease. Furthermore, in TLE patients, haGlyR and potassium chloride cotransporter 2 (KCC2) expressions were inversely regulated. To examine this potential causal relationship with respect to TLE histopathology, we established a hippocampal cell culture system utilising tonic inhibition mediated by haGlyRs in response to hippocam-pal ambient glycine and in the context of a high Cl equilibrium potential, as is the case in TLE hippocampal neurons. We showed that hypoactive neurons increase their ratio between glutamatergic and GABAergic synapses, reduce their dendrite length and finally undergo excitotoxicity. Pharmacological dissection of the underlying processes revealed ionotropic glutamate and TrkB receptors as critical mediators between neuronal hypoactivity and the emergence of these TLE-characteristic histopathological signs. Moreover, our results indicate a beneficial role for KCC2, because decreasing the Cl- equilibrium potential by KCC2 expression also rescued hypoactive hippocampal neurons. Thus, our data support a causal relationship between increased haGlyR expression and the emergence of histopathological TLE-characteristic signs, and they establish a pathophysiological role for neuronal hypoactivity in the context of a high Cl- equilibrium potential.
越来越多的癫痫患者患有耐药性颞叶癫痫（TLE），需要替代治疗方法。高亲和力甘氨酸受体（haGlyRs）由于对海马体周围甘氨酸的反应而在功能上适应强直抑制，并且其合成是活性依赖的。因此，在我们的研究中，我们扫描了TLE海马切除术标本中haGlyRs的表达，并使用原代海马神经元表征了这些受体介导的效应。在病情严重的患者的TLE海马体中出现了haGlyR表达增加。此外，在TLE患者中，haGlyR和氯化钾共转运体2（KCC2）的表达呈反向调节。为了研究这种与TLE组织病理学的潜在因果关系，我们建立了一个海马细胞培养系统，利用haGlyRs介导的强直抑制来响应海马体周围甘氨酸，并在高氯离子平衡电位的背景下进行，就像TLE海马神经元的情况一样。我们发现活性低下神经元增加了其谷氨酸能和GABA能突触之间的比例，缩短了其树突长度，最终发生兴奋性毒性。对潜在过程的药理学剖析揭示了离子型谷氨酸受体和TrkB受体是神经元活性低下与这些TLE特征性组织病理学体征出现之间的关键介质。此外，我们的结果表明KCC2具有有益作用，因为通过KCC2表达降低氯离子平衡电位也能挽救活性低下的海马神经元。因此，我们的数据支持haGlyR表达增加与TLE特征性组织病理学体征出现之间的因果关系，并在高氯离子平衡电位的背景下确立了神经元活性低下的病理生理作用。
