Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia
Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia
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DOI：
10.1523/jneurosci.2687-05.2005
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发表时间：
2005-10-19
影响因子：
5.3
通讯作者：
Baraban, SC
中科院分区：
文献类型：
--
作者：
Calcagnotto, ME;Paredes, MF;Baraban, SC
局灶性皮质发育不良(FCD)是医学上难治性癫痫的常见和重要原因。在颞叶癫痫患者和几种动物模型中，GABA介导的神经元抑制受损有助于癫痫的发生。尽管在FCD组织样本中GABA能中间神经元密度降低，但关于导致突触抑制的生理变化以及这些变化在发育异常的人脑中对癫痫发生的潜在贡献，几乎没有可用的信息。使用从FCD患者的组织切片中识别的神经元的可视化全细胞膜片钳记录，我们证明GABA(A)受体介导的抑制在异型增生区域发生了实质性的改变。这些改变包括IPSC频率的显著降低和转运体介导的GABA再摄取功能的潜在代偿性降低；后者的显著特征是诱发性和自发性IPSC的衰减时间常数显著增加，以及GABA转运抑制剂1-[2([(二苯亚甲基)imino]oxy)ethyl]-1，2，5，6-tetrahydro-3-pyridinecarboxylic酸盐酸盐)对IPSC动力学的影响不明显。免疫组织化学染色显示GABA能中间神经元散在分布于发育不良的皮质，GABA转运体的表达显著减少。综上所述，这些结果表明，GABA介导的突触抑制的深刻变化在FCD患者的癫痫发生过程中发挥了重要作用。
Focal cortical dysplasia (FCD) is a common and important cause of medically intractable epilepsy. In patients with temporal lobe epilepsy and in several animal models, compromised neuronal inhibition, mediated by GABA, contributes to seizure genesis. Although reduction in GABAergic interneuron density has been reported in FCD tissue samples, there is little available information on the resulting physiological changes in synaptic inhibition and the potential contribution of these changes to epileptogenesis in the dysplastic human brain. Using visualized whole-cell patch-clamp recordings from identified neurons in tissue slices obtained from patients with FCD, we demonstrate that GABA(A)-receptor- mediated inhibition is substantially altered in regions of dysplasia. These alterations include a significant reduction in IPSC frequency and a potentially compensatory decrease in transporter-mediated GABA reuptake function; the latter is marked by a significant increase in the decay-time constant for evoked and spontaneous IPSCs and a lack of effect of the GABA transport-inhibitor 1-[2([( diphenylmethylene) imino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride on IPSC kinetics. Immunohistochemical staining revealed a scattering of GABAergic interneurons across dysplastic cortex and striking reductions in GABA transporter expression. Together, these results suggest that profound alterations in GABA-mediated synaptic inhibition play an essential role in the process of epileptogenesis in patients with FCD.