GABA signaling in the neocortex in normal development and epilepsy

描述（由申请人提供）：新生儿期是癫痫发作发生率最高的时期，超过了人类寿命的所有其他时期。新生儿癫痫发作与不良神经系统结局（包括精神发育迟滞、行为障碍和癫痫）的高可能性相关。然而，仍不清楚癫痫发作相关损害中有多少继发于癫痫发作的病因或癫痫发作本身。在之前的资助期间（2002-2006年），我们定义了GABA在新生儿癫痫发作发生中的关键作用，表明在发育中的海马中，GABA的作用是复杂的，表现出兴奋性和抑制性。新生儿癫痫发作也会导致长期的认知障碍。虽然这项工作表明海马在癫痫发作和癫痫相关损害中起着重要作用，但临床研究表明，大多数严重癫痫儿童患有新皮质癫痫。值得注意的是，关于GABA是否在发育中的新皮层中也有双重作用，以及如果是这样，这如何影响正常的大脑发育和癫痫易感性，我们知之甚少。新生儿癫痫发作对新皮质功能的长期影响也不清楚。这项研究的总体目标是更好地了解GABA信号在正常和异常大脑发育中的作用，从细胞水平开始，并逐步发展到行为研究。这个延续的建议将围绕GABA信号在正常的早期发展，以及在癫痫发作期间的新皮层的作用。第一个具体的目标是研究大鼠新皮层中的GABA信号的发育变化。在此基础上，我们将研究发育过程中新皮层GABA信号的变化，包括GABA（A）逆转电位（EGABA）、GABA（A）驱动力（DFGABA）（即EGABA与膜电位（Em）之差）、动作电位阈值以及GABA作用中兴奋-抑制转换的变化。具体目标二将研究去极化GABA在未成熟新皮层产生生理和阵发性活动中的作用。我们将利用在前一个资助期间开发的新记录技术来研究GABA能诱导的发育中的新皮层的可塑性。第三个具体目标将使用强大的行为和体内电生理技术相结合来评估新生儿癫痫发作对新皮层功能的影响。具体而言，我们将评估新生儿癫痫发作对新皮层突触传递和前额叶皮层功能的长期影响。公共卫生相关性这项研究应该提供有价值的见解癫痫发作发生在发育中的大脑和大脑发育的后果，这种癫痫发作的机制。

DESCRIPTION (provided by applicant): The neonatal period eclipses all other epochs of the human life span for the highest incidence of seizures. Neonatal seizures are associated with a high likelihood of adverse neurological outcomes including mental retardation, behavioral disorders, and epilepsy. However, it remains unclear how much of the seizure- related damage is secondary to the etiology of the seizures or the seizures per se. In the prior funding period (2002-2006) we defined the critical role of GABA in seizure genesis in neonates, demonstrating that in the developing hippocampus the GABA effect is complex, showing both excitatory and inhibitory properties. Neonatal seizures were also found to result in long-standing cognitive impairment. While this work showed the hippocampus has an important role in seizure genesis and seizure-related impairment, clinical studies have shown that most children with severe epilepsy have neocortical epilepsy. Remarkably little is known about whether GABA also has a dual role in the developing neocortex, and if so, how this affects normal brain development and seizure susceptibility. The long-term effect of neonatal seizures on neocortical function is also not known. The overall goal of the study is to better understand the role of GABA signaling in normal and abnormal brain development, starting at the cellular level and progressing into behavioral studies. This continuation proposal will revolve around the role of GABA signaling in the neocortex in normal early development as well as during seizures The first specific aim is to study developmental changes in GABA signaling in the rat neocortex. In this aim we will determine the actual developmental changes in GABA signaling in the neocortex during development including the changes in GABA(A) reversal potential (EGABA), GABA(A) driving force (DFGABA, that is the difference between EGABA and membrane potential (Em), action potential threshold, and the excitatory-to-inhibitory switch in the action of GABA. Specific aim two will study the role of depolarizing GABA in the generation of physiological and paroxysmal activities in the immature neocortex. We will take advantage of novel recording techniques developed during the prior funding period to examine GABAergic induced plasticity in the developing neocortex. The third specific aim will evaluate the consequences of neonatal seizures on neocortical function using a combination of powerful behavioral and in vivo electrophysiological techniques. Specifically, we will assess the long-term effect of recurrent neonatal seizures on neocortical synaptic transmission and prefrontal cortex function. PUBLIC HEALTH RELEVANCE This study should provide valuable insights into the mechanisms by which seizures occur in the developing brain and the consequences of such seizures on brain development.