Pentney A R, Baraban S C, Colmers W F
Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
J Neurophysiol. 2002 Nov;88(5):2745-54. doi: 10.1152/jn.00500.2002.
Neuronal migration disorders (NMDs) can be associated with neurological dysfunction such as mental retardation, and clusters of disorganized cells (heterotopias) often act as seizure foci in medically intractable partial epilepsies. Methylazoxymethanol (MAM) treatment of pregnant rats results in neuronal heterotopias in offspring, especially in hippocampal area CA1. Although the neurons in dysplastic areas in this model are frequently hyperexcitable, the precise mechanisms controlling excitability remain unclear. Here, we used IR-DIC videomicroscopy and whole cell voltage-clamp techniques to test whether the potent anti-excitatory actions of neuropeptide Y (NPY) affected synaptic excitation of heterotopic neurons. We also compared several synaptic and intrinsic properties of heterotopic, layer 2-3 cortical, and CA1 pyramidal neurons, to further characterize heterotopic cells. NPY powerfully inhibited synaptic excitation onto normal and normotopic CA1 cells but was nearly ineffective on responses evoked in heterotopic cells from stimulation sites within the heterotopia. Glutamatergic synaptic responses on heterotopic cells exhibited a comparatively small, D-2-amino-5-phosphopentanoic acid-sensitive, N-methyl-D-aspartate component. Heterotopic neurons also differed from normal CA1 cells in postsynaptic membrane currents, possessing a prominent inwardly rectifying K(+) current sensitive to Cs(+) and Ba(2+), similar to neocortical layer 2-3 pyramidal cells. CA1 cells instead had a prominent Cs(+)- and 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride-sensitive I(h) and negligible inward rectification, unlike heterotopic cells. Thus heterotopic CA1 cells appear to share numerous physiological similarities with neocortical neurons. The lack of NPY's effects on intra-heterotopic inputs, the small contribution of I(h), and abnormal glutamate receptor function, may all contribute to the lowered threshold for epileptiform activity observed in hippocampal heterotopias and could be important factors in epilepsies associated with NMDs.
神经元迁移障碍（NMDs）可能与神经功能障碍如智力发育迟缓相关，并且紊乱细胞簇（异位）在药物难治性部分性癫痫中常作为癫痫病灶。用甲基偶氮甲醇（MAM）处理怀孕大鼠会导致后代出现神经元异位，尤其是在海马CA1区。尽管该模型中发育异常区域的神经元经常过度兴奋，但控制兴奋性的精确机制仍不清楚。在此，我们使用红外微分干涉对比视频显微镜和全细胞电压钳技术来测试神经肽Y（NPY）的强效抗兴奋作用是否会影响异位神经元的突触兴奋。我们还比较了异位、皮质第2 - 3层和CA1锥体细胞的几种突触和内在特性，以进一步表征异位细胞。NPY强烈抑制对正常和正常位置CA1细胞的突触兴奋，但对来自异位区内刺激位点诱发的异位细胞反应几乎无效。异位细胞上的谷氨酸能突触反应表现出相对较小的、对D - 2 - 氨基 - 5 - 磷酸戊酸敏感的N - 甲基 - D - 天冬氨酸成分。异位神经元在突触后膜电流方面也与正常CA1细胞不同，具有对Cs(+)和Ba(2+)敏感的突出内向整流钾电流，类似于新皮质第2 - 3层锥体细胞。相反，CA1细胞具有突出的对Cs(+)和4 - （N - 乙基 - N - 苯基氨基） - 1,2 - 二甲基 - 6 - （甲氨基）嘧啶氯化物敏感的I(h)且内向整流可忽略不计，这与异位细胞不同。因此，异位CA1细胞似乎与新皮质神经元具有许多生理相似性。NPY对异位区内输入缺乏作用、I(h)贡献小以及谷氨酸受体功能异常，可能都导致了在海马异位中观察到的癫痫样活动阈值降低，并且可能是与NMDs相关癫痫的重要因素。
