Franz Julia, Barheier Nicole, Wilms Henrike, Tulke Susanne, Haas Carola A, Häussler Ute
Experimental Epilepsy Research, Department of Neurosurgery, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Front Cell Neurosci. 2023 Mar 29;17:1142507. doi: 10.3389/fncel.2023.1142507. eCollection 2023.
Selective loss of inhibitory interneurons (INs) that promotes a shift toward an excitatory predominance may have a critical impact on the generation of epileptic activity. While research on mesial temporal lobe epilepsy (MTLE) has mostly focused on hippocampal changes, including IN loss, the subiculum as the major output region of the hippocampal formation has received less attention. The subiculum has been shown to occupy a key position in the epileptic network, but data on cellular alterations are controversial. Using the intrahippocampal kainate (KA) mouse model for MTLE, which recapitulates main features of human MTLE such as unilateral hippocampal sclerosis and granule cell dispersion, we identified cell loss in the subiculum and quantified changes in specific IN subpopulations along its dorso-ventral axis. We performed intrahippocampal recordings, FluoroJade C-staining for degenerating neurons shortly after (SE), fluorescence hybridization for glutamic acid decarboxylase ( mRNA and immunohistochemistry for neuronal nuclei (NeuN), parvalbumin (PV), calretinin (CR) and neuropeptide Y (NPY) at 21 days after KA. We observed remarkable cell loss in the ipsilateral subiculum shortly after SE, reflected in lowered density of NeuN+ cells in the chronic stage when epileptic activity occurred in the subiculum concomitantly with the hippocampus. In addition, we show a position-dependent reduction of -expressing INs by ∼50% (along the dorso-ventral as well as transverse axis of the subiculum). This particularly affected the PV- and to a lesser extent CR-expressing INs. The density of NPY-positive neurons was increased, but the double-labeling for mRNA expression revealed that an upregulation or expression of NPY in non-GABAergic cells with a concomitant reduction of NPY-positive INs underlies this observation. Our data suggest a position- and cell type-specific vulnerability of subicular INs in MTLE, which might contribute to hyperexcitability of the subiculum, reflected in epileptic activity.
抑制性中间神经元（INs）的选择性丧失会促使兴奋性占主导地位，这可能对癫痫活动的产生产生关键影响。虽然关于内侧颞叶癫痫（MTLE）的研究大多集中在海马体变化，包括INs丧失，但作为海马结构主要输出区域的下托受到的关注较少。下托已被证明在癫痫网络中占据关键位置，但关于细胞改变的数据存在争议。使用用于MTLE的海马内注射红藻氨酸（KA）小鼠模型，该模型概括了人类MTLE的主要特征，如单侧海马硬化和颗粒细胞弥散，我们确定了下托中的细胞损失，并量化了沿其背腹轴特定IN亚群的变化。我们进行了海马内记录，在癫痫持续状态（SE）后不久对退化神经元进行FluoroJade C染色，在KA后21天对谷氨酸脱羧酶（GAD）mRNA进行荧光原位杂交以及对神经元细胞核（NeuN）、小白蛋白（PV）、钙视网膜蛋白（CR）和神经肽Y（NPY）进行免疫组织化学检测。我们观察到SE后不久同侧下托有明显的细胞损失，这反映在慢性期NeuN+细胞密度降低，此时下托与海马体同时出现癫痫活动。此外，我们显示表达GAD的INs在位置上有依赖性减少约50%（沿下托的背腹轴以及横轴）。这尤其影响了表达PV的INs，对表达CR的INs影响较小。NPY阳性神经元的密度增加，但对GAD mRNA表达的双重标记显示，非GABA能细胞中NPY的上调或表达以及NPY阳性INs的同时减少是这一观察结果的基础。我们的数据表明MTLE中下托INs存在位置和细胞类型特异性的易损性，这可能导致下托的过度兴奋，表现为癫痫活动。
