GABA bouton subpopulations in the human dentate gyrus are differentially altered in mesial temporal lobe epilepsy
GABA bouton subpopulations in the human dentate gyrus are differentially altered in mesial temporal lobe epilepsy
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DOI：
10.1152/jn.00523.2018
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发表时间：
2020-01-01
影响因子：
2.5
通讯作者：
Richardson, R. Mark
中科院分区：
文献类型：
--
作者：
Alhourani, Ahmad;Fish, Kenneth N.;Richardson, R. Mark
医学上难治性颞叶癫痫是一种毁灭性的疾病，手术切除癫痫发作区是唯一已知的治愈方法。多项研究发现人类内侧颞叶癫痫（MTLE）存在异常齿状回网络回路的证据。齿状回内的主要神经元将内嗅输入门控到海马，提供信息处理的关键步骤。对该作用至关重要的是GABA表达神经元，特别是表达小清蛋白（PV）的篮状细胞（PVBC）和枝形细胞（PVChCs），它们提供强的、时间协调的抑制信号。在癫痫中已经描述了PVBC和PVChC扣结的改变，但是由于与研究人体组织相关的方法学障碍，这些研究的价值受到限制。我们开发了一种多标记免疫荧光共聚焦显微镜和自定义分割算法，以定量评估PVBC和PVChC的终扣密度，并推断人类齿状回的相对突触蛋白含量。使用整块标本MTLE受试者与海马硬化和不与非癫痫对照配对，我们证明了这种方法的实用性检测细胞类型特异性突触改变。具体来说，我们发现增加密度的PVBC扣，而PVChC扣显著减少，在海马硬化症的受试者与匹配的对照组相比，在齿状核颗粒细胞层。相比之下，没有硬化的癫痫受试者和匹配的对照组之间PV阳性细胞类型的终末密度没有差异。这些结果可能解释了以前研究中相互矛盾的结果，这些研究报告了PV终扣密度的保留和减少，并建立了定量评估癫痫中中间神经元终扣的新标准。新&值得注意的是一种最先进的多标记免疫荧光共聚焦显微镜和自定义分割算法技术，以前开发用于研究人类前额叶皮层中的突触，对颞叶癫痫患者手术切除的海马齿状回进行了研究。作者发现，在内侧颞叶癫痫患者中，人类齿状回的枝状和篮状细胞扣结发生了不同的改变。
Medically intractable temporal lobe epilepsy is a devastating disease, for which surgical removal of the seizure onset zone is the only known cure. Multiple studies have found evidence of abnormal dentate gyrus network circuitry in human mesial temporal lobe epilepsy (MTLE). Principal neurons within the dentate gyrus gate entorhinal input into the hippocampus, providing a critical step in information processing. Crucial to that role are GABA-expressing neurons, particularly parvalbumin (PV)-expressing basket cells (PVBCs) and chandelier cells (PVChCs), which provide strong, temporally coordinated inhibitory signals. Alterations in PVBC and PVChC boutons have been described in epilepsy, but the value of these studies has been limited due to methodological hurdles associated with studying human tissue. We developed a multilabel immunofluorescence confocal microscopy and a custom segmentation algorithm to quantitatively assess PVBC and PVChC bouton densities and to infer relative synaptic protein content in the human dentate gyrus. Using en bloc specimens from MTLE subjects with and without hippocampal sclerosis, paired with nonepileptic controls, we demonstrate the utility of this approach for detecting cell-type specific synaptic alterations. Specifically, we found increased density of PVBC boutons, while PVChC boutons decreased significantly in the dentate granule cell layer of subjects with hippocampal sclerosis compared with matched controls. In contrast, bouton densities for either PV-positive cell type did not differ between epileptic subjects without sclerosis and matched controls. These results may explain conflicting findings from previous studies that have reported both preserved and decreased PV bouton densities and establish a new standard for quantitative assessment of interneuron boutons in epilepsy.NEW & NOTEWORTHY A state-of-the-art, multilabel immunofluorescence confocal microscopy and custom segmentation algorithm technique, developed previously for studying synapses in the human prefrontal cortex, was modified to study the hippocampal dentate gyrus in specimens surgically removed from patients with temporal lobe epilepsy. The authors discovered that chandelier and basket cell boutons in the human dentate gyrus are differentially altered in mesial temporal lobe epilepsy.