Redecker C, Luhmann H J, Hagemann G, Fritschy J M, Witte O W
Department of Neurology and Institute of Neurophysiology, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
J Neurosci. 2000 Jul 1;20(13):5045-53. doi: 10.1523/JNEUROSCI.20-13-05045.2000.
Focal cortical malformations comprise a heterogeneous group of disturbances of brain development, commonly associated with drug-resistant epilepsy and/or neuropsychological deficits. Electrophysiological studies on rodent models of cortical malformations demonstrated intrinsic hyperexcitability in the lesion and the structurally intact surround, indicating widespread imbalances of excitation and inhibition. Here, alterations in regional expression of GABA(A) receptor subunits were investigated immunohistochemically in adult rats with focal cortical malformations attributable to neonatal freeze-lesions. These lesions are morphologically characterized by a three- to four-layered cortex with microsulcus formation. Widespread regionally differential reduction of GABA(A) receptor subunits alpha1, alpha2, alpha3, alpha5, and gamma2 was observed. Within the cortical malformation, this downregulation was most prominent for subunits alpha5 and gamma2, whereas medial to the lesion, a significant and even stronger decrease of all subunits was detected. Lateral to the dysplastic cortex, the decrease was most prominent for subunit gamma2 and moderate for subunits alpha1, alpha2, and alpha5, whereas subunit alpha3 was not consistently altered. Interestingly, the downregulation of GABA(A) receptor subunits also involved the ipsilateral hippocampal formation, as well as restricted contralateral neocortical areas, indicating widespread disturbances in the neocortical and hippocampal network. The described pattern of downregulation of GABA(A) receptor subunits allows the conclusion that there is a considerable modulation of subunit composition. Because alterations in subunit composition critically influence the electrophysiological and pharmacological properties of GABA(A) receptors, these alterations might contribute to the widespread hyperexcitability and help to explain pharmacotherapeutic characteristics in epileptic patients.
局灶性皮质发育畸形是一组异质性的脑发育障碍，通常与药物难治性癫痫和/或神经心理缺陷相关。对皮质发育畸形啮齿动物模型的电生理研究表明，病变部位及其结构完整的周围区域存在内在性兴奋性过高，提示兴奋和抑制广泛失衡。在此，采用免疫组织化学方法研究了成年大鼠因新生期冷冻损伤所致局灶性皮质发育畸形中γ-氨基丁酸A（GABA(A)）受体亚基区域表达的变化。这些损伤在形态学上的特征是具有微沟形成的三至四层皮质。观察到GABA(A)受体亚基α1、α2、α3、α5和γ2在区域上广泛存在差异减少。在皮质发育畸形内，亚基α5和γ2的下调最为显著，而在病变内侧，所有亚基均有显著且更强烈的减少。在发育异常皮质的外侧，亚基γ2的减少最为显著，亚基α1、α2和α5的减少为中度，而亚基α3则无一致变化。有趣的是，GABA(A)受体亚基的下调还涉及同侧海马结构以及对侧有限的新皮质区域，提示新皮质和海马网络存在广泛紊乱。所描述的GABA(A)受体亚基下调模式表明亚基组成存在相当大的调节。由于亚基组成的改变会严重影响GABA(A)受体的电生理和药理学特性，这些改变可能导致广泛的兴奋性过高，并有助于解释癫痫患者的药物治疗特征。
