Avoli Massimo, Benini Ruba, de Guzman Philip, Omar Amer
Departments of Neurology and Neurosurgery, and of Physiology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4.
Neuropharmacology. 2004 Jan;46(1):43-51. doi: 10.1016/s0028-3908(03)00307-1.
Rat brain slices containing interconnected hippocampus and entorhinal cortex (EC) responded to 4-aminopyridine (50 microM) application by generating: (i) CA3-driven interictal discharges that propagated to the EC; and (ii) N-methyl-D-aspartic (NMDA) acid receptor-dependent ictal events originating in EC (cf. J. Neurosci. 17 (1997) 9308 for experiments made in brain slices). Ictal discharges disappeared within 1-2 h, but were re-established by cutting the Schaffer collaterals, which abolished CA3-driven interictal discharge propagation to EC. In intact slices, GABA(B) receptor activation by baclofen (5-40 microM): (i) depressed CA3-driven interictal activity; and (ii) disclosed non-NMDA glutamatergic receptor-dependent ictal discharges originating in CA3 and propagating to EC. These effects were reversed by the GABA(B) receptor antagonist CGP 35348 (0.5 mM). Application of increasing baclofen doses to slices in which hippocampus and EC networks were surgically isolated decreased epileptiform events with an IC50 that was lower in EC (0.6 microM; n = 12) than in CA3 (2.5 microM; n = 12). Hence, under control conditions, EC ictogenesis depends on NMDA receptor function and is controlled by CA3-driven output activity; in contrast, following GABA(B) receptor activation EC excitability is depressed to a greater extent than CA3, which leads to non-NMDA glutamatergic receptor-mediated ictogenesis in CA3. We propose that GABA(B) receptor modulation may represent an important mechanism for setting the site of initiation, the modalities of propagation and the glutamatergic receptor properties of ictogenesis in the limbic system and, perhaps, in mesial temporal lobe epilepsy patients.
包含相互连接的海马体和内嗅皮质（EC）的大鼠脑切片，在施加4-氨基吡啶（50微摩尔）后会产生以下反应：（i）由CA3驱动的间歇性放电，并传播至EC；以及（ii）起源于EC的N-甲基-D-天冬氨酸（NMDA）受体依赖性发作性事件（参见《神经科学杂志》17卷（1997年）9308页关于脑切片实验的内容）。发作性放电在1 - 2小时内消失，但通过切断谢弗侧支可重新建立，切断谢弗侧支会消除CA3驱动的间歇性放电向EC的传播。在完整切片中，巴氯芬（5 - 40微摩尔）激活GABA(B)受体：（i）抑制CA3驱动的间歇性活动；以及（ii）揭示了起源于CA3并传播至EC的非NMDA谷氨酸能受体依赖性发作性放电。这些效应可被GABA(B)受体拮抗剂CGP 35348（0.5毫摩尔）逆转。向海马体和EC网络手术分离的切片中增加巴氯芬剂量，可减少癫痫样事件，其半数抑制浓度（IC50）在EC中（0.6微摩尔；n = 12）低于CA3中（2.5微摩尔；n = 12）。因此，在对照条件下，EC的癫痫发作形成依赖于NMDA受体功能，并受CA3驱动的输出活动控制；相反，在GABA(B)受体激活后，EC的兴奋性比CA3受到更大程度的抑制，这导致CA3中出现非NMDA谷氨酸能受体介导的癫痫发作形成。我们提出，GABA(B)受体调节可能是设定边缘系统以及或许内侧颞叶癫痫患者癫痫发作起始部位、传播方式和癫痫发作形成的谷氨酸能受体特性的重要机制。
