Predictors of Seizure-Induced Memory Impairment

描述（由申请人提供）：癫痫持续状态（SE）的严重后果是记忆障碍。然而，对这种认知缺陷的病理生理机制知之甚少。暴露大鼠在青春期早期癫痫持续状态的原因损害的空间记忆在水迷宫，并在平行，显着异常的位置细胞的位置放电模式和稳定性，这种模式。这些发现证实了最近的工作，证明了位置细胞的持续活动和大鼠在空间任务中充分执行的能力之间的密切关系。因此，位置细胞可以作为空间记忆的细胞水平指示器，空间记忆是大鼠海马的一种非常高水平的认知功能。这项研究的一个主要目标是严格测试位置细胞异常是诱导大鼠实验性癫痫后观察到的空间记忆障碍的标志物。我们的第一个目的是确定位置细胞异常的时间后SE在成年大鼠，并比较这个时间过程中的空间记忆和大脑兴奋性的变化的时间。在这一目标中，我们将比较海马位置细胞功能（放电率，精度和稳定性）的变化与认知功能和海马兴奋性的变化的时间过程中的海马神经元诱导的变化。SE后提出的一个关键问题是，复发性癫痫发作或发作间期癫痫样放电（棘波和尖波）是否会进一步损害认知功能。位置细胞研究为我们提供了在单细胞水平上检查癫痫发作和尖峰对认知功能的影响的机会。使用机械导向的假说，我们将确定自发性复发性癫痫发作和发作间期癫痫样活动后SE改变位置细胞功能。了解癫痫引起的认知障碍的机制的关键一步是确定位置细胞和视觉空间记忆障碍是否延伸到其他癫痫发作损伤。我们的第三个目的是评估连续癫痫发作对位置细胞功能的影响，连续癫痫发作导致水迷宫性能受损，但与SE相比具有明显不同的病理模式。总之，这些研究将提供深入了解糖尿病诱导的认知功能障碍的机制，这将是至关重要的，因为我们试图开发新的治疗干预措施。

DESCRIPTION (provided by applicant): A serious consequence of status epilepticus (SE) is memory impairment. Yet, remarkably little is known about the pathophysiological mechanisms responsible for this cognitive deficit. Exposing rats to status epilepticus during early adolescence causes impairment of spatial memory in the water maze and, in parallel, marked abnormalities in both the positional firing patterns of place cells and the stability of such patterns. These findings corroborate recent work demonstrating strong relationships between the ongoing activity of place cells and the ability of rats to perform adequately in spatial tasks. Thus, place cells may serve as a cell-level indicator of spatial memory, a very high level cognitive function of the rat hippocampus. A major goal of the studies proposed in this grant application is to rigorously test the idea that place cell abnormalities are markers of spatial memory impairment seen after induction of experimental epilepsy in rats. Our first aim is to determine the timing of place cell abnormalities following SE in adult rats and to compare this time course with the timing of changes in spatial memory and cerebral excitability. In this aim we will compare the time course of seizure-induced changes in hippocampal place cell function (firing rates, precision, and stability) with changes in cognitive function and hippocampal excitability. A critical question asked following SE is whether recurrent seizures or interictal epileptiform discharges (spikes and sharp waves) further harm cognitive function. Place cell studies provide us with the opportunity to examine the effects of seizures and spikes on cognitive function at the single cell level. Using mechanistically-oriented hypotheses we will determine whether spontaneous recurrent seizures and interictal epileptiform activity following SE alters place cell function. A key step in understanding the mechanisms of seizure-induced cognitive deficits is to determine whether place cell and visual-spatial memory impairment extend to other seizure insults. Our third aim is to assess the effects of serial seizures, which result in impaired water maze performance but have a distinctly different pathological pattern than SE, on place cell function. Taken together these studies will provide insight into the mechanisms of seizure-induced cognitive dysfunction which will be critical as we attempt to develop novel therapeutic interventions.