Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma

描述(申请人提供)：这项研究的目的是了解为什么大脑皮层损伤经常导致阵发性活动。在颅脑损伤后24小时内，高达80%的穿透伤患者出现临床癫痫发作。这种急性癫痫发作往往引发癫痫的发生，这是一种阈值以下的过程，导致自发的、反复发作的发作，并最终导致癫痫。我们建议在体内、体外和与实验密切相关的计算模型中研究慢性实验中创伤诱发癫痫的电生理特征。我们将测试的癫痫发生原因的主要假设是，创伤相关的慢性活动阻断可能激活内稳态可塑性机制，上调去极化影响(如兴奋性内在和突触电导)，下调超极化影响(如抑制性电导)。在创伤皮质中发现的异常情况下，这可能会造成不稳定的平衡，导致阵发性癫痫发作。将使用多点局部场电位记录(最高可达通道)来验证以下假设：侵袭性脑损伤会产生不同的、兴奋不足和过度兴奋的皮质区域，并且这些区域的相互作用会增加癫痫发生的可能性。通过测量Mini、突触反应性、轴突分支、固有细胞特性和多部位焦域电位的变化，将获得动态平衡可塑性在癫痫发生中的作用的直接证据。将在中期(天)和长期(周)进行测量。将在加拿大拉瓦尔大学进行体内电生理学、半时间和慢性实验，以及来自慢性去传入皮层脑片的体外实验以及形态学研究。将使用索尔克研究所的独立成分分析(ICA)研究增加脑损伤后癫痫发作可能性的条件的数据，并将其纳入加州大学河滨分校的霍奇金-赫胥黎皮质神经元和网络的Hodgkin-Huxley类型模型。计算模型的目标是探索癫痫发生期间在体内皮质发生的所有变化之间的相互作用，并预测可以防止癫痫发作的干预措施。这些干预措施的设计将基于可以进一步开发的方法，以在临床环境中治疗患有创伤诱发癫痫的人类。公共卫生相关性：在24小时内，高达80%的头部穿透伤患者出现临床癫痫发作。越南战争和克罗地亚战争后，大约50%的颅骨穿透伤患者在10-15年后出现以反复发作为特征的癫痫。认识和预防癫痫的发生是癫痫研究的中心问题。

DESCRIPTION (provided by applicant): The goal of this research is to understand why cerebral cortical trauma often leads to paroxysmal activity. Within 24 hours following head injury, up to 80% of patients with penetrating wounds display clinical seizures. Such acute seizures often initiate epileptogenesis the subthreshold processes that lead to spontaneous, recurring seizures and ultimately to epilepsy. We propose to study the electrophysiological features of trauma- induced epileptogenesis in chronic experiments in vivo, in vitro and with computational models that will be developed in close contact with the experiments. The primary hypothesis for the cause of epileptogenesis that we will test is that trauma-related chronic blockade of activity may activate homeostatic plasticity mechanisms that upregulate depolarizing influences (such as excitatory intrinsic and synaptic conductances) and downregulate hyperpolarizing ones (such as inhibitory conductances). Under the abnormal conditions found in traumatized cortex, this may create an unstable balance that leads to paroxysmal seizures. Multisite local field potential recordings (up to 64 channels) will be used to test the hypothesis that invasive brain trauma creates heterogeneous under- and overexcited cortical areas and that interaction of these areas increases the likelihood of seizure occurrence. Direct evidence for the role of homeostatic plasticity in the epileptogenesis will be obtained by measuring changes in minis, synaptic responsiveness, axonal arborization, intrinsic cellular properties, and multisite focal field potentials. Measurement will be performed over the medium-term (days) and long-term (weeks). In vivo electrophysiological semichronic and chronic experiments, in vitro experiments from chronically deafferented cortical slices as well as morphological studies will be performed at Laval University (Canada). Data from studying the conditions that increase the likelihood of seizure development after brain trauma will be studied using Independent Component Analysis (ICA) at the Salk Institute and will be incorporated into Hodgkin-Huxley type models of cortical neurons and networks at the UC Riverside. The goal of the computational models is to explore the interplay between all of the changes that occur in the cortex in vivo during epileptogenesis and to make predictions for interventions that could prevent seizures. The design of these interventions will be based on approaches that could be further developed to treat humans with trauma-induced epilepsy in clinical settings. PUBLIC HEALTH RELEVANCE: Within 24 hours up to 80% of patients with penetrating head wounds display clinical seizures. Following the Vietnam and Croatia wars, approximately 50% of patients with penetrating cranial wounds developed epilepsy characterized by recurring seizures 10-15 years later. Understanding and preventing epileptogenesis is a central problem in epilepsy research.