A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Institute of Molecular and Cellular Pharmacology, Medical University Innsbruck, Peter-Mayr-Str. 1, 6020 Innsbruck, Austria.
Neuroscience. 2021 Nov 1;475:52-72. doi: 10.1016/j.neuroscience.2021.08.018. Epub 2021 Aug 26.
Traumatic brain injury (TBI) causes 10-20% of structural epilepsy, with seizures typically originating in the cortex. Alterations in the neuronal microcircuits in the cortical epileptogenic zone, however, are poorly understood. Here, we assessed TBI-induced changes in perisomatic gamma aminobutyric acid (GABA)-ergic innervation in the perilesional cortex. We hypothesized that TBI will damage parvalbumin (PV)-immunoreactive inhibitory neurons and induce regulation of the associated GABAergic molecular interactome. TBI was induced in adult male Sprague-Dawley rats by lateral fluid-percussion injury. At 1-month post-TBI, the number of PV-positive somata was plotted on unfolded cortical maps and the distribution and density of immunopositive terminals analyzed. Qualitative analysis revealed either patchy microlesions of several hundred micrometers in diameter or diffuse neuronal loss. Quantitative analysis demonstrated a reduction in the number of PV-positive interneurons in patches down to 0% of that in sham-operated controls in the perilesional cortex. In the majority of patches, the cell numbers ranged from 71% to 90% that of the controls. The loss of PV-positive somata was accompanied by decreased axonal labeling. In situ hybridization revealed downregulated PV mRNA expression in the perilesional cortex. Gene Set Enrichment Analysis indicated a robustly downregulated expression profile of PV-related genes, which was confirmed by quantitative reverse transcriptase polymerase chain reaction. Specifically, we found that genes encoding postsynaptic GABA-A receptor genes, Gabrg2 and Gabrd, were downregulated in TBI animals compared with controls. Our data suggests that patchy reduction in PV-positive perisomatic inhibitory innervation contributes to the development of focal cortical inhibitory deficit after TBI.
创伤性脑损伤（TBI）导致 10-20%的结构性癫痫，癫痫发作通常起源于皮质。然而，皮质致痫区神经元微电路的改变尚不清楚。在这里，我们评估了 TBI 引起的皮质损伤区周围 GABA 能传入的变化。我们假设 TBI 将损伤 PV 免疫反应性抑制性神经元，并诱导相关 GABA 能分子相互作用组的调节。通过侧脑室液压冲击损伤诱导成年雄性 Sprague-Dawley 大鼠 TBI。在 TBI 后 1 个月，将 PV 阳性体的数量绘制在展开的皮质图上，并分析免疫阳性终末的分布和密度。定性分析显示直径数百微米的微局灶性微损伤或弥漫性神经元丢失。定量分析表明，损伤区周围皮质中 PV 阳性中间神经元的数量减少到 sham 对照组的 0%。在大多数病灶中，细胞数量范围为对照的 71%至 90%。PV 阳性体的丢失伴随着轴突标记的减少。原位杂交显示损伤区周围皮质中 PV mRNA 表达下调。基因集富集分析表明 PV 相关基因的表达谱明显下调，这通过定量逆转录聚合酶链反应得到证实。具体来说，我们发现编码突触后 GABA-A 受体基因 Gabrg2 和 Gabrd 的基因在 TBI 动物中表达下调。我们的数据表明，PV 阳性体周围抑制性传入的局灶性减少导致 TBI 后局灶性皮质抑制缺陷的发展。
