Luhmann H J, Karpuk N, Qü M, Zilles K
Institute of Neurophysiology, University of Düsseldorf, D-40001 Dusseldorf, Germany.
J Neurophysiol. 1998 Jul;80(1):92-102. doi: 10.1152/jn.1998.80.1.92.
Neuronal migration disorders (NMD) are involved in a variety of different developmental disturbances and in therapy-resistant epilepsy. The cellular mechanisms underlying the pronounced hyperexcitability in dysplastic cortex are not well understood and demand further clinical and experimental analyses. We used a focal freeze-lesion model in cerebral cortex of newborn rats to study the functional consequences of NMD. Intracellular recordings from supragranular regular spiking cells in cortical slices from adult sham-operated rats revealed normal passive and active intrinsic membrane properties and normal stimulus-evoked excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs, respectively). Regular spiking neurons recorded in rat dysplastic cortex showed on average a significantly smaller action potential amplitude, a slower spike rise, and a less steep primary frequency-current relationship. Stimulus-elicited EPSPs in NMD-affected cortex consisted of multiphasic burst discharges, which coincided with extracellular field potentials and lasted 150-800 ms. These epileptiform responses could be recorded at membrane potentials between -50 and -110 mV and were blocked by -2-amino-5-phosphonovaleric acid (APV), indicating the involvement of N-methyl--aspartate (NMDA) receptors. Isolated NMDA-mediated and APV-sensitive EPSPs could be recorded at membrane potentials negative to -70 mV, suggesting that NMDA receptors are activated at relatively negative membrane potentials. In comparison with the controls, polysynaptic IPSPs mediated by the gamma-aminobutyric acid (GABA) type A and B receptor were either absent or reduced in peak conductance in microgyric cortex by 27% (P < 0.05) and 17%, respectively. However, monosynaptic IPSPs recorded in the presence of ionotropic glutamate receptor antagonists revealed a similar efficacy in NMD and control cortex, indicating that GABAergic neurons in microgyric cortex get a weaker excitatory input. Our data indicate that the expression of epileptiform activity in NMD-affected cortex rather results from an imbalance between excitatory and inhibitory synaptic transmission than from alterations in the intrinsic membrane properties. This imbalance is caused by an increase in NMDA-receptor-mediated excitation in pyramidal neurons and a concurrent decrease of glutamatergic input onto inhibitory interneurons.
神经元迁移障碍（NMD）与多种不同的发育紊乱以及难治性癫痫有关。发育异常的皮质中明显的过度兴奋性背后的细胞机制尚未完全了解，需要进一步的临床和实验分析。我们使用新生大鼠大脑皮质的局灶性冷冻损伤模型来研究NMD的功能后果。来自成年假手术大鼠皮质切片中颗粒上层规则放电细胞的细胞内记录显示，被动和主动内在膜特性正常，刺激诱发的兴奋性和抑制性突触后电位（分别为EPSP和IPSP）也正常。在大鼠发育异常的皮质中记录的规则放电神经元平均显示出明显较小的动作电位幅度、较慢的峰电位上升以及较不陡峭的初级频率-电流关系。在受NMD影响的皮质中，刺激诱发的EPSP由多相爆发性放电组成，这与细胞外场电位一致，持续150 - 800毫秒。这些癫痫样反应可在膜电位为-50至-110 mV之间记录到，并被2-氨基-5-磷酸戊酸（APV）阻断，表明N-甲基-D-天冬氨酸（NMDA）受体参与其中。在膜电位负于-70 mV时可记录到分离的NMDA介导的且对APV敏感的EPSP，这表明NMDA受体在相对负的膜电位时被激活。与对照组相比，由A型和B型γ-氨基丁酸（GABA）受体介导的多突触IPSP在微小脑回皮质中要么不存在，要么峰值电导分别降低了27%（P < 0.05）和17%。然而，在离子型谷氨酸受体拮抗剂存在的情况下记录的单突触IPSP在NMD和对照皮质中显示出相似的效能，这表明微小脑回皮质中的GABA能神经元获得较弱的兴奋性输入。我们的数据表明，受NMD影响的皮质中癫痫样活动的表达更多是由于兴奋性和抑制性突触传递之间的失衡，而非内在膜特性的改变。这种失衡是由锥体神经元中NMDA受体介导的兴奋增加以及抑制性中间神经元上谷氨酸能输入的同时减少引起的。
