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，对皮质致痫区神经元微电路的改变知之甚少。在这里，我们评估了 TBI 诱导的病灶周围皮层中 perisomatic γ-氨基丁酸 (GABA)-能神经支配的变化。我们假设 TBI 会损伤小清蛋白 (PV) 免疫反应性抑制神经元并诱导相关 GABA 能分子相互作用组的调节。通过横向流体冲击损伤在成年雄性 Sprague-Dawley 大鼠中诱导 TBI。在 TBI 后 1 个月，将 PV 阳性胞体的数量绘制在展开的皮质图上，并分析免疫阳性末端的分布和密度。定性分析显示直径数百微米的斑片状微病变或弥漫性神经元丢失。定量分析表明，斑块中 PV 阳性中间神经元的数量减少到病灶周围皮层假手术对照的 0%。在大多数贴片中，细胞数量为对照的 71% 至 90%。PV 阳性胞体的丧失伴随着轴突标记的减少。原位杂交显示病灶周围皮层中 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，这通过定量逆转录酶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受体的基因的基因，GABRG2和Gabrd，是在TBI动物下调与对照组相比。我们的数据表明，PV 阳性 perisomatic 抑制神经支配的斑驳减少有助于 TBI 后局灶性皮质抑制缺陷的发展。