Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis
Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis
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DOI：
10.1016/j.nbd.2017.08.008
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发表时间：
2017-12-01
影响因子：
6.1
通讯作者：
Prince, David A.
中科院分区：
文献类型：
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作者：
Gu, Feng;Parada, Isabel;Prince, David A.
在损伤诱导的新皮层癫痫发生的部分皮层隔离（“底切”或“UC”）模型中的电生理实验表明，突触前末梢异常可导致GABA能突触传递的改变。为了确定抑制的降低是否与GABA能中间神经元的结构异常相关，我们在UC和对照感觉运动大鼠皮层中使用免疫细胞化学技术、共聚焦显微镜和EM来分析快速尖峰的含小白蛋白的中间神经元和第V层的锥体（Pyr）细胞的结构改变。1）UC皮质中小白蛋白（PV）或GABA免疫反应中间神经元的计数没有减少，而VGAT和GAD-65和GAD-67在第V层Pyr胞体周围GABA能终末晕中的表达显著降低。与以前的结果一致，体细胞的大小和密度的Pyr细胞减少，在颗粒下层的UC皮层。3)充满生物胞素的FS中间神经元的树突体积显著减少。4)UC中充满生物细胞素的FS细胞轴突中GABA能终扣的大小和VGAT含量减少，与突触后桥蛋白的共定位减少，表明GABA能突触减少。第V层Pyr胞体的定量EM证实了抑制性突触的减少。5)UC皮质Pyr细胞的脑源性神经营养因子（BDNF）-IR和-mRNA显著和持续降低，PV细胞的TrkB-IR降低。6)结果导致这样的假设，即来自Pyr细胞的BDNF的营养支持的减少可能有助于UC皮质中FS细胞的轴突终末和树突的退行性变化以及GABA能抑制的减少。皮质结构损伤是癫痫的主要原因，约占一般人群病例的20%，战时脑外伤人员发病率高达-50%。GABA能抑制性中间神经元的丢失是与脑外伤和其他病因后癫痫发生相关的重要病理生理因素。这些实验的结果表明，最大的人口皮质中间神经元，小白蛋白含有快速尖峰（FS）的中间神经元，保留在部分癫痫的部分新皮层隔离模型。然而，这些细胞的轴突终末结构异常，GABA合成酶和囊泡GABA转运体含量减少，与锥体神经元形成的突触减少。这些结构异常是GABA能神经传递缺陷的基础，GABA能神经传递是电生理实验中发现的癫痫发生的关键病理生理因素。BDNF及其TrkB受体是维持中间神经元和锥体神经元的关键因子，在受损的皮质中减少。结果表明，供应BDNF受伤的致痫性脑可能会扭转结构和功能异常的小白蛋白FS中间神经元，并提供抗癫痫治疗。(C)2017爱思唯尔公司All rights reserved.
Electrophysiological experiments in the partial cortical isolation ("undercut" or "UC") model of injury-induced neocortical epileptogenesis have shown alterations in GABAergic synaptic transmission attributable to abnormalities in presynaptic terminals. To determine whether the decreased inhibition was associated with structural abnormalities in GABAergic interneurons, we used immunocytochemical techniques, confocal microscopy and EM in UC and control sensorimotor rat cortex to analyze structural alterations in fast-spiking parvalbumin-containing interneurons and pyramidal (Pyr) cells of layer V. Principle findings were: 1) there were no decreases in counts of parvalbumin (PV)- or GABA-immunoreactive interneurons in UC cortex, however there were significant reductions in expression of VGAT and GAD-65 and-67 in halos of GABAergic terminals around Pyr somata in layer V. 2) Consistent with previous results, somatic size and density of Pyr cells was decreased in infragranular layers of UC cortex. 3) Dendrites of biocytin-filled FS interneurons were significantly decreased in volume. 4) There were decreases in the size and VGAT content of GABAergic boutons in axons of biocytin-filled FS cells in the UC, together with a decrease in colocalization with postsynaptic gephyrin, suggesting a reduction in GABAergic synapses. Quantitative EM of layer V Pyr somata confirmed the reduction in inhibitory synapses. 5) There were marked and lasting reductions in brain derived neurotrophic factor (BDNF)-IR and-mRNA in Pyr cells and decreased TrkB-IR on PV cells in UC cortex. 6) Results lead to the hypothesis that reduction in trophic support by BDNF derived from Pyr cells may contribute to the regressive changes in axonal terminals and dendrites of FS cells in the UC cortex and decreased GABAergic inhibition.Significance: Injury to cortical structures is a major cause of epilepsy, accounting for about 20% of cases in the general population, with an incidence as high as-50% among brain-injured personnel in wartime. Loss of GABAergic inhibitory intemeurons is a significant pathophysiological factor associated with epileptogenesis following brain trauma and other etiologies. Results of these experiments show that the largest population of cortical interneurons, the parvalbumin-containing fast-spiking (FS) interneurons, are preserved in the partial neocortical isolation model of partial epilepsy. However, axonal terminals of these cells are structurally abnormal, have decreased content of GABA synthetic enzymes and vesicular GABA transporter and make fewer synapses onto pyramidal neurons. These structural abnormalities underlie defects in GABAergic neurotransmission that are a key pathophysiological factor in epileptogenesis found in electrophysiological experiments. BDNF, and its TrkB receptor, key factors for maintenance of interneurons and pyramidal neurons, are decreased in the injured cortex. Results suggest that supplying BDNF to the injured epileptogenic brain may reverse the structural and functional abnormalities in the parvalbumin FS interneurons and provide an antiepileptogenic therapy. (C) 2017 Elsevier Inc. All rights reserved.