Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma

描述（由申请人提供）：本研究的目的是了解为什么大脑皮质创伤经常导致阵发性活动。在头部受伤后的24小时内，高达80%的穿透伤患者会出现临床癫痫发作。这种急性发作通常会引发阈下过程的癫痫发生，导致自发性、反复发作并最终导致癫痫。我们建议在体内、体外的慢性实验中研究创伤性癫痫发生的电生理特征，并建立与实验密切相关的计算模型。我们将测试的癫痫发生原因的主要假设是，与创伤相关的慢性活动阻断可能激活稳态可塑性机制，从而上调去极化影响（如兴奋性内在和突触传导），下调超极化影响（如抑制性传导）。在受到创伤的大脑皮层中发现的异常情况下，这可能会造成不稳定的平衡，从而导致阵发性癫痫发作。多位点局部场电位记录（多达64个通道）将被用于测试侵入性脑创伤产生异质的皮层兴奋不足和过度兴奋区域以及这些区域的相互作用增加癫痫发作可能性的假设。体内平衡可塑性在癫痫发生中的作用的直接证据将通过测量最小值、突触反应性、轴突树突化、内在细胞特性和多位点焦场电位的变化来获得。测量将在中期（天）和长期（周）进行。在体内进行半慢性和慢性电生理实验，在体外进行慢性去神经皮质切片实验以及形态学研究。索尔克研究所将使用独立成分分析（ICA）来研究脑外伤后癫痫发作可能性增加的情况，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模型。计算模型的目标是探索在癫痫发生过程中发生在体内皮层的所有变化之间的相互作用，并预测可以预防癫痫发作的干预措施。这些干预措施的设计将基于可在临床环境中进一步发展用于治疗创伤性癫痫患者的方法。公共卫生相关性：在24小时内，高达80%的头部穿透伤患者表现为临床癫痫发作。在越南和克罗地亚战争之后，大约50%的颅骨穿透伤患者在10-15年后发生癫痫，其特征是反复发作。了解和预防癫痫发生是癫痫研究的核心问题。

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.