Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures
Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures
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DOI：
10.1152/jn.00682.2006
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发表时间：
2006-12-01
影响因子：
2.5
通讯作者：
Leresche, Nathalie
中科院分区：
文献类型：
--
作者：
Bessaih, Thomas;Bourgeais, Laurence;Leresche, Nathalie
人体和实验研究表明，GABA（A）受体的分子遗传变化可能是失神发作期间棘波放电（SWD）表达的基础。然而，这些癫痫发作背后的遗传缺陷的全谱仅被部分阐明，丘脑皮质网络内假定的异常蛋白的表达和功能谱尚未确定，并且这些蛋白导致失神发作的病理生理机制知之甚少。在这里，我们研究了关键的丘脑皮质区，即，在来自斯特拉斯堡的遗传性失神癫痫大鼠（GAERS）（一种典型失神癫痫发作的成熟遗传模型，未显示额外的神经异常）中，对躯体感觉皮层、腹侧基底丘脑（VB）和丘脑网状核（NRT）进行了研究，并将其特性与年龄匹配的非癫痫对照（NECs）进行了比较。VB和皮层第II/III层神经元的微型GABA（A）IPSC在GAERS和NEC中相似，而在GAERS NRT神经元中，它们的振幅大25%，衰减快40%。此外，巴氯芬在降低GAERS中NRT mIPSC频率方面的效果显著低于NEC，而在两种菌株之间未观察到皮质和VB mIPSCS的差异。GAERS NRT的成对脉冲抑制小45%，但VB中没有，并且对GABA（B）拮抗剂不敏感。这些结果表明，在典型失神发作的SWD中存在微妙的、核特异性的GABA（A）受体异常，而不是这些受体在整个丘脑皮质网络中的完全阻断，并且它们在癫痫发作前的发生表明它们可能具有致癫痫意义。
Human and experimental studies indicate that molecular genetic changes in GABA(A) receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABA(A) inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABA(A) IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABA(B) antagonists. These results point to subtle, nucleus-specific, GABA(A) receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.