GABA signaling in the neocortex in normal development and epilepsy

描述(由申请人提供)：新生儿期是癫痫发病率最高的时期，超过了人类生命中的所有其他时期。新生儿癫痫发作与包括智力低下、行为障碍和癫痫在内的不良神经后果的可能性很高。然而，目前尚不清楚与癫痫发作相关的损害中有多少是癫痫发作的病因或癫痫发作本身的次要损害。在之前的资助期间(2002-2006)，我们定义了GABA在新生儿癫痫发生中的关键作用，表明在发育中的海马体中，GABA的效应是复杂的，既表现出兴奋特性，也表现出抑制特性。新生儿癫痫发作也被发现会导致长期的认知障碍。虽然这项工作表明，海马体在癫痫的发生和癫痫相关的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都患有新皮质癫痫。值得注意的是，关于GABA是否也在发育中的新皮质中起双重作用，以及如果是的话，这如何影响正常的大脑发育和癫痫易感性，人们知之甚少。新生儿癫痫发作对新皮质功能的长期影响也尚不清楚。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，并进展到行为研究。这一继续的建议将围绕GABA信号在新皮质中的作用，在正常的早期发育以及癫痫发作期间，第一个特定的目的是研究大鼠新皮质中GABA信号的发育变化。为此，我们将确定新皮质中GABA信号在发育过程中的实际发育变化，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作用下兴奋性到抑制性开关的变化。具体目标二将研究去极化GABA在未成熟新皮质产生生理和阵发性活动中的作用。我们将利用在之前的资助期间开发的新的记录技术来检测GABA能在发育中的新皮质中的可塑性。第三个具体目标将使用强大的行为和活体电生理技术相结合来评估新生儿癫痫发作对新皮质功能的影响。具体地说，我们将评估反复发作的新生儿癫痫对新皮质突触传递和前额叶皮质功能的长期影响。公共卫生相关性这项研究应该为癫痫在发育中的大脑中发生的机制以及这种癫痫发作对大脑发育的后果提供有价值的见解。

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.