GABA Neuron Subpopulation and the Regulation of Cortical Neuronal and Behavior

项目4的总体目标是描述疾病相关的神经生理和行为 表型在两个遗传模型的发展interneuronopathies：细胞周期蛋白D2无效和Six 3- Cre：Projs中开发的音刺猬（Shh）通路的Smo（FI/FI）条件无效。1和2中所示。 由Projs 1、2和4以及Core B提供的解剖学数据表明，这两种遗传模型在以下方面不同： 就其对MGE衍生的中间神经元的影响而言，至少在2个重要方面：1）相对减少， 小清蛋白表达（Pv+）与生长抑素表达（SSN+）亚群和2）差异效应 大脑皮层和海马区具体地说，细胞周期蛋白D2模型表现出Pv+的损失，但不是 SSN+中间神经元在皮质;此外，海马显示出更显着的减少，在Pv+ interneurons，相对于neocortical区域。另一方面，Six 3-Cre：Smo（FI/FI）模型显示损失 在新皮层和海马两者中均存在Pv+和SSN+中间神经元。在项目4中， 将使用电生理学， 功能解剖学和行为实验。电生理学实验将检验这一假设 在这些突变小鼠的新皮层和海马体中，局部GABA传输减少。的 行为实验将描述癫痫发作阈值和恐惧相关行为的变化 GABAA-苯二氮卓受体的功效降低。行为与大脑皮层的相关性 神经元活动将通过行为动物的基于遥测的EEG和通过量化诱导来评估 在给予负性调节细胞凋亡的配体后立即早期基因c-fos的模式， GABAA-BZ受体。这些研究将共同描述特定的“发育不良”的影响， 中间神经元亚群对出生后前额叶和边缘皮质回路功能发育的影响 调节情绪调节（特别是恐惧）和癫痫易感性。 新皮层和海马的中间神经元群体的病理发育被认为是 导致几种大脑发育障碍，包括癫痫发作、认知障碍、自闭症和 精神分裂症临床前研究支持这样的观点，即情感症状和认知缺陷， 通常伴随这些疾病，也可能部分由皮质GABA的破坏介导。 传播或其发展后果。因此，项目4对癫痫症具有广泛的相关性， 情绪和认知障碍。

The overarching goal of Project 4 is to characterize disease-relevant neurophysiological and behavioral phenotypes in two genetic models of developmental interneuronopathies: Cyclin D2 nulls and the Six3- Cre:Smo(FI/FI) conditional nulls of the sonic hedgehog (Shh) pathway developed in Projs. 1 and 2, respectively. Anatomical data provided by Projs 1,2 and 4 and Core B indicate that these two genetic models differ in terms of their impact on MGE-derived interneurons in at least 2 important aspects: 1) relative decreases in parvalbumin-expressing (Pv+) vs. somatostatin-expressing (SSN+) subpopulations and 2) differential effects on neocortical and hippocampal subregions. Specifically, the cyclin D2 model exhibits a loss of Pv+ but not SSN+ interneurons in the cortex; moreover the hippocampus shows a more marked reduction in Pv+ interneurons, relative to neocortical regions. On the other hand, the Six3-Cre:Smo(FI/FI) model shows a loss of both Pv+ and SSN+ interneurons in both neocortex and hippocampus. In Project 4, the impact of these different patterns of interneuron deficits will be determined using a combination of electophysiological, functional-anatomical, and behavioral experiments. Electrophysiological experiments will test the hypothesis that local GABA transmission is reduced in the neocortex and hippocampus of these mutant mice. The behavioral experiments will characterize changes in seizure threshold and fear-related behaviors in response to decreases in efficacy of the GABAA-benzodiazepine receptor. Correlations between behavior and cortical neuron activity will be assessed by telemetry-based EEGs in behaving animals and by quantifying induction patterns of the immediate early gene c-fos following administration of ligands that negatively modulate the GABAA-BZ receptor. Together these studies will characterize the impact of the "maldevelopment" of specific interneuron subpopulations on the functional postnatal development of prefrontal and limbic cortical circuitry mediating mood regulation (specifically, fear) and seizure susceptibility. Pathological development of interneuron populations of the neocortex and hippocampus are thought to contribute to several developmental brain disorders including seizures, cognitive disabilities, autism and schizophrenia. Preclinical research supports the idea that the affective symptoms and cognitive deficits that often accompany these disorders may also be, in part, mediated by a disruption of cortical GABA transmission or its developmental consequences. Thus Project 4 has broad relevance for epilepsy and disorders of mood and cognition.