Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3BG, UK.
Neuroscience. 2011 Oct 27;194:208-19. doi: 10.1016/j.neuroscience.2011.07.074. Epub 2011 Aug 4.
Traumatic brain injury (TBI) is a risk factor for the development of epilepsy, which can occur months to years after the insult. The hippocampus is particularly vulnerable to the pathophysiological effects of TBI. Here, we determined whether there are long-term changes in inhibition in the dentate gyrus that could contribute to the progressive susceptibility to seizures after TBI. We used severe lateral-fluid percussion brain injury to induce TBI in rats. In this model, spontaneous seizure activity, which involves the hippocampus, appears after a long latent period, resembling the human condition. We demonstrate that synaptic GABA(A) receptor-mediated inhibition is profoundly reduced in ipsilateral dentate granule cells 1 month after TBI. Moreover, synaptic inhibition decreases over time, and by 6 months after TBI, it is also significantly decreased contralaterally. Progressive loss of synaptic inhibition is paralleled by a decline in the number of parvalbumin-positive interneurons, but, in contrast to status epilepticus models, GABA(A) receptor subunit expression is largely unaltered. At both time points, the magnitude of tonic GABA(A) receptor-mediated currents after TBI is maintained, indicating a preservation of the inhibitory constraint of granule cells through tonic inhibition. Our results extend the time window during which strategies to target epileptogenesis may be effective.
创伤性脑损伤 (TBI) 是癫痫发生的一个风险因素，癫痫可能在损伤后数月至数年发生。海马体特别容易受到 TBI 的病理生理影响。在这里，我们确定在 TBI 后是否存在齿状回抑制的长期变化，这可能导致癫痫的逐渐易感性。我们使用严重的外侧液击脑损伤来诱导大鼠的 TBI。在这种模型中，涉及海马体的自发性癫痫活动在很长的潜伏期后出现，类似于人类的情况。我们证明，TBI 后 1 个月，同侧齿状回颗粒细胞中的突触 GABA(A) 受体介导的抑制显著降低。此外，抑制作用随时间推移而逐渐减弱，TBI 后 6 个月时，对侧抑制作用也明显降低。突触抑制的逐渐丧失与囊泡相关蛋白阳性中间神经元数量的减少平行，但与癫痫持续状态模型不同，GABA(A) 受体亚基表达基本不变。在这两个时间点，TBI 后强直 GABA(A) 受体介导的电流幅度保持不变，表明通过强直抑制保持了颗粒细胞的抑制约束。我们的结果扩展了针对癫痫发生的策略可能有效的时间窗口。
