Leung Wai Lam, Shad Ali, Perucca Piero, O'Brien Terence J, Semple Bridgette D, Casillas-Espinosa Pablo M
Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia.
Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia; Department of Neurology, Alfred Health, Melbourne, VIC 3004, Australia; Department of Immunology & Pathology, Monash University, Melbourne, VIC 3004, Australia.
Epilepsy Behav. 2025 May;166:110347. doi: 10.1016/j.yebeh.2025.110347. Epub 2025 Feb 28.
Post-traumatic epilepsy (PTE) is a common, serious, long-term complication of traumatic brain injury (TBI). However, only a minority of individuals will develop epilepsy after a TBI, and the contribution of genetic predisposition to the risk of acquired epilepsy warrants further exploration. In this study, we examined whether innate, genetically determined differences in seizure susceptibility between seizure-prone FAST and seizure-resistant SLOW rat strains would influence chronic behavioral and PTE outcomes after experimental TBI. We hypothesized that FAST rats would show increased vulnerability to PTE and poorer neurobehavioral outcomes. Using the lateral fluid percussion injury model, we first determined the optimal injury parameters to generate a mild-moderate TBI in young adult FAST rats, which had previously shown high mortality to severe TBI. Then, FAST and SLOW rats underwent TBI or sham surgery, and a series of behavioral tests were performed either acutely (within 4 weeks) or chronically (more than 22 weeks) post-injury. Acutely, FAST rats showed an increased physiological response to TBI with a longer apnea duration, delayed pain response, and delayed self-righting, as well as increased acute seizure-like behavior compared to SLOW rats. Conversely, SLOW rats showed greater neuromotor deficits and weight loss sub-acutely compared to FAST rats. Chronically, while strain-specific phenotypes were observed (e.g., FAST rats showing increased anxiety-like behavior, altered nociceptive responses, and polydipsia), no TBI effects were detected. Analysis of continuous video-electroencephalographic recordings over a 1-month period starting at 6 months post-TBI did not reveal any spontaneous seizures. However, periodic epileptiform discharges were only found in FAST rats that had a TBI. Together, these findings reflect fundamental differences in chronic behavior and epileptiform discharges as a result of innate distinctions in epileptogenic susceptibility in FAST versus SLOW rats. However, a lack of spontaneous seizure activity or chronic neurobehavioral deficits in TBI animals confounded our ability to address the initial hypothesis, such that alternative injury models may be more suitable to study genetic contributions to the development of PTE.
创伤后癫痫（PTE）是创伤性脑损伤（TBI）常见、严重的长期并发症。然而，仅有少数个体在TBI后会发生癫痫，遗传易感性对后天性癫痫风险的影响值得进一步探究。在本研究中，我们检验了癫痫易感的FAST大鼠品系和抗癫痫的SLOW大鼠品系之间，由基因决定的先天性癫痫易感性差异是否会影响实验性TBI后的慢性行为和PTE结局。我们假设FAST大鼠对PTE的易感性会增加，神经行为结局会更差。使用侧方流体冲击伤模型，我们首先确定了在年轻成年FAST大鼠中产生轻-中度TBI的最佳损伤参数，此前这些大鼠对重度TBI显示出高死亡率。然后，FAST和SLOW大鼠接受TBI或假手术，并在损伤后急性（4周内）或慢性（超过22周）进行一系列行为测试。急性情况下，与SLOW大鼠相比，FAST大鼠对TBI的生理反应增强，呼吸暂停持续时间更长，疼痛反应延迟，翻正反射延迟，急性癫痫样行为也增加。相反，与FAST大鼠相比，SLOW大鼠在亚急性期表现出更大的神经运动缺陷和体重减轻。慢性情况下，虽然观察到了品系特异性表型（例如，FAST大鼠表现出焦虑样行为增加、伤害性反应改变和烦渴），但未检测到TBI效应。对TBI后6个月开始的1个月连续视频脑电图记录分析未发现任何自发性癫痫发作。然而，仅在有TBI的FAST大鼠中发现了周期性癫痫样放电。总之，这些发现反映了FAST大鼠与SLOW大鼠在癫痫易感性上的先天性差异导致的慢性行为和癫痫样放电的根本差异。然而，TBI动物缺乏自发性癫痫活动或慢性神经行为缺陷，这混淆了我们验证最初假设的能力，因此替代损伤模型可能更适合研究遗传因素对PTE发生发展的影响。
