Luhmann H J, Raabe K, Qü M, Zilles K
Institute of Neurophysiology, University of Düsseldorf, Germany.
Eur J Neurosci. 1998 Oct;10(10):3085-94. doi: 10.1046/j.1460-9568.1998.00311.x.
The majority of patients showing neuronal migration disorders in cortical structures suffer from pharmaco-resistant epilepsy. In order to study the molecular and cellular mechanisms underlying this pronounced hyperexcitability, we used an animal model of focal cortical dysplasia demonstrating structural malformations which resemble the human pathology of microgyria. Neocortical slices prepared from adult rats, which at the day of birth received a cortical freeze lesion, were analysed in vitro with an array of eight extracellular recording electrodes to investigate the pattern and pharmacology of propagating epileptiform activity in microgyric cortex. In cortical slices exhibiting neuronal migration disorders, orthodromic synaptic stimulation elicited late recurrent activity and early epileptiform responses that spread with 0.06 m/s over > or = 3.5 mm across the cortex. Application of a N-methyl-D-aspartate (NMDA) antagonist blocked the late recurrent activity, but not the propagation of the early epileptiform responses. The latter were blocked by an (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist, indicating that the spread of this activity was predominantly mediated by activation of AMPA receptors. A very similar response pattern could be observed in neocortical slices obtained from untreated age-matched control rats, when the slice was partially disinhibited by bath-application of 5 microM bicuculline methiodide. Stimulus-evoked epileptiform signals recorded in disinhibited slices propagated with 0.08 m/s across the cortex and showed the same sensitivity to ionotropic glutamate antagonists as in dysplastic cortex. Our results indicate that widespread structural and/or functional modifications of the AMPA receptor and possibly also of the gamma-amino-butyric acid type A receptor contribute to the pronounced hyperexcitability in dysplastic cortex.
大多数在皮质结构中表现出神经元迁移障碍的患者患有药物难治性癫痫。为了研究这种明显的过度兴奋性背后的分子和细胞机制，我们使用了局灶性皮质发育异常的动物模型，该模型显示出类似于人类微小脑回病理的结构畸形。从出生当天接受皮质冷冻损伤的成年大鼠制备新皮质切片，在体外使用一组八个细胞外记录电极进行分析，以研究微小脑回皮质中癫痫样活动传播的模式和药理学。在表现出神经元迁移障碍的皮质切片中，顺向突触刺激引发晚期复发活动和早期癫痫样反应，这些反应以0.06 m/s的速度在皮质上传播超过或等于3.5 mm。应用N-甲基-D-天冬氨酸（NMDA）拮抗剂可阻断晚期复发活动，但不能阻断早期癫痫样反应的传播。后者可被（±）-α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）拮抗剂阻断，表明这种活动的传播主要由AMPA受体的激活介导。当通过浴加5 microM甲硫酸荷包牡丹碱使切片部分去抑制时，从未经处理的年龄匹配对照大鼠获得的新皮质切片中可观察到非常相似的反应模式。在去抑制切片中记录的刺激诱发的癫痫样信号以0.08 m/s的速度在皮质上传播，并且对离子型谷氨酸拮抗剂的敏感性与发育异常皮质中的相同。我们的结果表明，AMPA受体以及可能还有A型γ-氨基丁酸受体的广泛结构和/或功能改变导致发育异常皮质中明显的过度兴奋性。
