Prince D A, Jacobs K M, Salin P A, Hoffman S, Parada I
Stanford University School of Medicine, Department of Neurology and Neurological Sciences, CA 94305-5300, USA.
Can J Physiol Pharmacol. 1997 May;75(5):500-7.
Several lines of evidence have suggested that decreases in postsynaptic inhibition may have a role in epileptogenesis in cortical structures. However, other studies have suggested that GABAergic inhibition is spared, or even augmented in some forms of post-lesional epilepsy. In the studies described here, inhibitory events were recorded in two models of post-lesional chronic epileptogenesis. (i) As previously reported (D.A. Prince and G.-F. Tseng. J. Neurophysiol. 69: 1276-1291. 1993), epileptiform activity develops in slices from partially isolated rat neocortical islands 2-3 weeks after the initial in vivo lesion. In this model of post-traumatic epilepsy, large amplitude polyphasic inhibitory postsynaptic currents (IPSCs) in layer V pyramidal neurons are associated with each interictal epileptiform field potential. The frequency of spontaneous IPSCs as well as miniature IPSCs was significantly increased in neocortical slices from the epileptogenic chronically injured cortex versus controls. Immunocytochemical reactions for parvalbumin and calbindin, calcium binding proteins present in subgroups of GABAergic neurons, showed an increased staining of both neuropil and somata within the epileptogenic tissue. Immunoreactivity for glutamic acid decarboxylase (GAD) and GABA also appeared to be increased in the neuropil. (ii) Cortical microgyri resembling human malformations were produced by freeze lesions made transcranially in P0 rat cortex (K.M. Jacobs, M.J. Gutnick, and D.A. Prince. Cereb. Cortex, 6: 514-523. 1996). The boundary between the four-layered microgyrus and surrounding cortex become epileptogenic within about 2 weeks, as judged by evoked extracellular field potentials and cellular activities. Epileptogenesis in the surrounding cortex is not altered when the microgyrus itself is isolated by transcortical cuts. Patch-clamp recordings from layer V neurons in the epileptogenic zone showed that spontaneous IPSCs are larger and more dependent on glutamatergic synapses than in control neurons. The amplitudes of polysynaptic IPSCs evoked by threshold stimulation were also larger than in control cells. Although evaluation of inhibitory events in these models is still incomplete, results to date suggest that GABAergic inhibition may be enhanced in epileptogenic areas associated with chronic cortical injury. Sprouting of axonal arborizations of pyramidal cells onto interneurons, upregulation of GABAergic neurons, and perhaps sprouting of inhibitory axons that make increased numbers of contacts onto pyramidal cells may all contribute to the increased inhibitory drive. Results in these models do not support the disinhibitory hypothesis of chronic epileptogenesis.
多条证据表明，突触后抑制的降低可能在皮质结构的癫痫发生中起作用。然而，其他研究表明，γ-氨基丁酸（GABA）能抑制得以保留，甚至在某些形式的损伤后癫痫中增强。在本文所述的研究中，在两种损伤后慢性癫痫发生模型中记录了抑制性事件。（i）如先前报道（D.A. Prince和G.-F. Tseng. 《神经生理学杂志》69: 1276 - 1291. 1993），在最初的体内损伤后2 - 3周，部分分离的大鼠新皮质岛的切片中会出现癫痫样活动。在这种创伤后癫痫模型中，V层锥体神经元中的大幅度多相抑制性突触后电流（IPSCs）与每个发作间期癫痫样场电位相关。与对照组相比，来自致痫性慢性损伤皮质的新皮质切片中自发IPSCs以及微小IPSCs的频率显著增加。对小白蛋白和钙结合蛋白（存在于GABA能神经元亚群中的钙结合蛋白）的免疫细胞化学反应显示，致痫组织内神经毡和胞体的染色均增加。神经毡中谷氨酸脱羧酶（GAD）和GABA的免疫反应性似乎也增加了。（ii）通过在出生后0天的大鼠皮质经颅冷冻损伤产生类似于人类畸形的皮质微小脑回（K.M. Jacobs、M.J. Gutnick和D.A. Prince. 《大脑皮质》，6: 514 - 523. 1996）。根据诱发的细胞外场电位和细胞活动判断，四层微小脑回与周围皮质之间的边界在大约2周内变得具有致痫性。当微小脑回本身通过跨皮质切割分离时，周围皮质的癫痫发生没有改变。对致痫区V层神经元的膜片钳记录显示，与对照神经元相比，自发IPSCs更大且更依赖于谷氨酸能突触。阈下刺激诱发的多突触IPSCs的幅度也大于对照细胞。尽管对这些模型中抑制性事件的评估仍不完整，但迄今为止的结果表明，与慢性皮质损伤相关的致痫区域中GABA能抑制可能增强。锥体细胞轴突分支向中间神经元的芽生、GABA能神经元的上调，以及可能抑制性轴突的芽生（使其与锥体细胞的接触数量增加）都可能导致抑制性驱动增加。这些模型中的结果不支持慢性癫痫发生的去抑制假说。
