GABA Neuron Subpopulation and the Regulation of Cortical Neuronal and Behavior

项目4的首要目标是描述与疾病相关的神经生理和行为 发育性神经元间病变两种遗传模型的表型：细胞周期蛋白D2缺失和Six3- Cre：在Projs中发育的Sonic Hedgehog(Shh)通路的SMO(FI/FI)条件空。分别为1和2。 Projs 1、2和4以及Core B提供的解剖数据表明，这两种遗传模式在 它们对MGE来源的中间神经元的影响至少在两个重要方面：1)相对减少 表达小白蛋白(PV+)和表达生长抑素(SSN+)的亚群及2)差异效应 在新皮质和海马亚区。具体地说，Cyclin D2模型显示出PV+的损失，但没有 皮质内的SSN+中间神经元；此外，海马区PV+的减少更为明显 中间神经元，相对于新皮质区域。另一方面，Six3-CRE：SMO(FI/FI)模型显示出 新皮质和海马区均有PV+和SSN+中间神经元。在项目4中，这些项目的影响 不同类型的神经元间缺陷将使用电生理学， 功能解剖学和行为学实验。电生理实验将验证这一假设 这些突变小鼠的大脑皮层和海马区的局部GABA传递减少。这个 行为学实验将表征癫痫阈值的变化和恐惧相关行为的反应 以降低GABAA-苯二氮卓类受体的疗效。行为与大脑皮层的相关性 神经元的活动将通过基于遥测的脑电对行为动物的脑电进行评估，并通过量化诱导 直接早期基因c-fos在给药后的模式负性调节 GABAA-BZ受体。这些研究将共同刻画特定疾病“发育不良”的影响。 中间神经元亚群对前额叶和边缘皮质回路功能生后发育的影响 调节情绪调节(具体地说，恐惧)和癫痫敏感性。 新皮质和海马区中间神经元群的病理发育被认为是 导致多种发育性大脑疾病，包括癫痫、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 通常伴随着这些疾病，也可能部分地由皮质GABA的破坏所介导 传播或其发展后果。因此，项目4与癫痫有广泛的相关性， 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.