Rutecki Paul A, Sayin Umit, Yang Yili, Hadar Eldad
Department of Neurology, William Middleton VA Hospital, University of Wisconsin, 2500 Overlook Trail, Madison, WI 53605, USA.
Epilepsia. 2002;43 Suppl 5:179-83. doi: 10.1046/j.1528-1157.43.s.5.34.x.
The transition from an interictal to an ictal pattern of epileptiform activity is a strategic target for antiepileptic drug (AED) action. Both the muscarinic agonist pilocarpine and the selective group I metabotropic glutamate receptor (mGluR) agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) produce prolonged synchronous activity in the hippocampal slice that resembles ictal discharges. We evaluated the role of synaptic mechanisms and release of calcium from intracellular stores in the generation of prolonged ictal oscillations.
Pilocarpine (10 microM) in 7.5 mM[K+]o or DHPG (100 microM) in 5 mM[K+]o artificial cerebrospinal fluid (ACSF) were bath applied to hippocampal slices, and extracellular recordings were made from the CA3 region. The pattern of activity was characterized as ictal if prolonged oscillations of discharges occurred at >2 Hz lasting for >3 s. The pattern of epileptiform activity was characterized and compared with the pattern observed after bath application of pharmacologic agents.
The AMPA/kainic acid (KA) glutamate receptor blocker DNQX (20 microM) dampened and stopped ictal oscillations; however, antagonism of N-methyl-d-aspartate (NMDA) or gamma-aminobutyric acid (GABAA) receptors had minimal effects on ictal patterns. Ictal discharges were suppressed by dantrolene (30-100 microM), which blocks release of calcium from intracellular stores, or thapsigargin (1-5 microM), which inhibits the adenosine triphosphatase (ATPase) that maintains intracellular calcium stores. The L-type calcium channel antagonist nifedipine (1 microM) blocked ictal activity produced by pilocarpine or DHPG.
Ictal discharges produced by pilocarpine or DHPG depended on intact synaptic transmission mediated by AMPA/KA receptors, release of calcium from intracellular stores, and L-type calcium channel activation. The results suggest that muscarinic and group I mGluRs activate a positive-feedback system that creates calcium oscillations and prolonged neuronal synchronization mediated by recurrent excitatory synaptic connections in the CA3 region of the hippocampus.
癫痫样活动从发作间期模式向发作期模式的转变是抗癫痫药物（AED）作用的一个关键靶点。毒蕈碱激动剂毛果芸香碱和选择性I组代谢型谷氨酸受体（mGluR）激动剂（RS）-3,5-二羟基苯甘氨酸（DHPG）均可在海马切片中产生类似于发作期放电的长时间同步活动。我们评估了突触机制和细胞内钙库释放钙在长时间发作期振荡产生中的作用。
将含10 μM毛果芸香碱的7.5 mM [K⁺]ₒ或含100 μM DHPG的5 mM [K⁺]ₒ人工脑脊液（ACSF）浴应用于海马切片，并从CA3区进行细胞外记录。如果放电的长时间振荡频率>2 Hz且持续时间>3 s，则将活动模式表征为发作期。对癫痫样活动模式进行表征，并与浴应用药物后观察到的模式进行比较。
AMPA/ kainic acid（KA）谷氨酸受体阻滞剂DNQX（20 μM）可抑制并终止发作期振荡；然而，N-甲基-D-天冬氨酸（NMDA）或γ-氨基丁酸（GABAA）受体的拮抗作用对发作期模式影响极小。丹曲林（30 - 100 μM）可抑制发作期放电，丹曲林可阻断细胞内钙库释放钙，或毒胡萝卜素（1 - 5 μM）可抑制维持细胞内钙库的腺苷三磷酸酶（ATPase）。L型钙通道拮抗剂硝苯地平（1 μM）可阻断毛果芸香碱或DHPG产生的发作期活动。
毛果芸香碱或DHPG产生的发作期放电依赖于由AMPA/KA受体介导的完整突触传递、细胞内钙库释放钙以及L型钙通道激活。结果表明，毒蕈碱和I组mGluRs激活了一个正反馈系统，该系统通过海马CA3区的反复兴奋性突触连接产生钙振荡并延长神经元同步。
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