Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy
Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy
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DOI：
10.1093/brain/awn095
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发表时间：
2008-06-01
期刊：
影响因子：
14.5
通讯作者：
Behr, Joachim
中科院分区：
文献类型：
--
作者：
Knopp, Andreas;Frahm, Christiane;Behr, Joachim
临床和实验证据表明，下托在颞叶癫痫发作的维持中起着重要作用。本研究采用匹罗卡品颞叶癫痫模型，探讨GABA能下叶中间神经元对反复发作的易感性及其功能意义。在毛果芸香碱处理的动物的下托中，谷氨酸脱羧酶（GAD）mRNA阳性细胞的密度在所有层中降低。我们的数据表明，在锥体细胞和分子层的小清蛋白免疫反应神经元的大量损失，而钙蛋白免疫反应细胞主要减少在分子层。虽然毛果芸香碱处理的大鼠下托表现出GAD 65免疫反应性的强度增加，在锥体细胞层中含有GAD 65的突触终末的密度降低，表明存活的突触终末的GAD 65强度增加。我们观察到介导树突抑制的诱发抑制性突触后电流减少，以及限制在体周区域的微型抑制性突触后电流（mIPSC）频率下降。mIPSC频率的降低（~ 30%）与体周GAD阳性终末的数量减少（~ 28%）相匹配，表明癫痫动物中突触前GABA能输入到锥体细胞的减少。虽然在下托的细胞损失还没有被认为是人类和实验性TLE的致病因素，我们的数据表明，下托GABA能中间神经元的脆弱性导致下托抑制系统的输入特异性干扰。
Clinical and experimental evidence suggest that the subiculum plays an important role in the maintenance of temporal lobe seizures. Using the pilocarpine-model of temporal lobe epilepsy (TLE), the present study examines the vulnerability of GABAergic subicular interneurons to recurrent seizures and determines its functional implications. In the subiculum of pilocarpine-treated animals, the density of glutamic acid decarboxylase (GAD) mRNA-positive cells was reduced in all layers. Our data indicate a substantial loss of parvalbumin-immunoreactive neurons in the pyramidal cell and molecular layer whereas calretinin-immunoreactive cells were predominantly reduced in the molecular layer. Though the subiculum of pilocarpine-treated rats showed an increased intensity of GAD65 immunoreactivity, the density of GAD65 containing synaptic terminals in the pyramidal cell layer was decreased indicating an increase in the GAD65 intensity of surviving synaptic terminals. We observed a decrease in evoked inhibitory post-synaptic currents that mediate dendritic inhibition as well as a decline in the frequency of miniature inhibitory post-synaptic currents (mIPSCs) that are restricted to the perisomatic region. The decrease in mIPSC frequency (-30%) matched with the reduced number of perisomatic GAD-positive terminals (-28%) suggesting a decrease of pre-synaptic GABAergic input onto pyramidal cells in epileptic animals. Though cell loss in the subiculum has not been considered as a pathogenic factor in human and experimental TLE, our data suggest that the vulnerability of subicular GABAergic interneurons causes an input-specific disturbance of the subicular inhibitory system.