Morphogenesis and Function of the Cerebral Cortex

描述（由申请人提供）：前额皮质（PFC）及其相关区域的异常神经元活动水平被认为是严重神经精神综合征症状的基础，包括精神分裂症、自闭症、妥瑞氏综合征和药物滥用障碍。我们研究计划的长期目标是了解在产前和产后发育过程中，兴奋性和抑制性皮层神经元的相对比例是如何被调节的。我们之前的研究表明，成纤维细胞生长因子（Fgf）信号上调兴奋性皮层神经元数量，导致前额叶和颞叶区域的体积扩大。初步数据表明，胚胎发育过程中Fgf受体2 （Fgfr2）增加了SVZ中“中间”祖细胞的数量，这反过来又与pfc中锥体神经元的发生有关。相反，Fgf受体1 （Fgfr1）不参与产前皮质发育，但可能通过出生后胶质细胞的作用增加皮质小白蛋白+和生长抑素+抑制性中间神经元的分化或存活。在这个竞争性延续的提议中，我们假设胚胎发生中的Fgfr2信号通过刺激放射状胶质细胞在SVZ中产生中间祖细胞来扩大PFC的表面积。这将在Specific Aim 1中通过追踪在产前发育的特定阶段诱导的含有Fgfr2等位基因缺失的放射状胶质细胞的后代来进行测试。此外，将比较缺乏Fgfr2的小鼠与Fgfr1、Fgf2和Fgf3联合缺失的小鼠之间的一般皮质形态发生。Fgf受体刺激和阻断对已鉴定的放射状胶质细胞的影响也将通过电穿孔显性阴性和显性活性Fgf受体来评估，这些Fgf受体由特定的放射状胶质启动子驱动。在特定目标2和3中，我们将评估神经胶质细胞中的Fgf信号是否间接促进表达小白蛋白（PV）和生长抑素（ST）的皮质抑制性神经元的存活或功能成熟，以及这种作用的发育时间窗。在Aim 2中，我们将把GFP+野生型中间神经元移植到Fgfr1突变小鼠的出生后皮层中，以确定Fgfr1突变小鼠皮层是否不太允许中间神经元成熟。我们还将评估Fgfr1突变小鼠移植和内源性中间神经元的内在放电特性和突触整合到皮质网络。在特定目标3中，我们将在产前或产后发育阶段通过病毒诱导或暂时调节Fgfr1重组特异性灭活GFAP+细胞中的Fgfr1，并检查中间神经元的成熟和存活。总之，这些实验将阐明特定的Fgf受体如何在生命的不同时期发挥特定的作用。前额皮质发育异常被认为是精神分裂症、自闭症、注意力缺陷多动和吸毒成瘾症状的基础。本研究旨在探讨FGF家族的生长因子如何通过控制SVZ前体皮层投射神经元的发生来建立大脑皮层的初级结构。该项目还侧重于神经胶质在出生后大脑皮层发育过程中抑制性中间神经元成熟中的作用。这两个方面都可能为纠正或逆转存在于神经精神和冲动控制障碍的大脑皮层中的兴奋性和抑制性神经元失衡提供有希望的线索。

DESCRIPTION (provided by applicant): Abnormal level of neuronal activity in the prefrontal cortex (PFC) and connected regions is thought to underlie the symptoms of serious neuropsychiatric syndromes, including schizophrenia, autism, Tourette's syndrome and substance abuse disorders. The long- term goal of our research program is to understand how the relative proportions of excitatory and inhibitory cortical neurons are regulated during pre- and post-natal development. Our previous studies have shown that Fibroblast Growth Factor (Fgf) signaling upregulates excitatory cortical neuron number, leading to volume expansion in prefrontal and temporal regions. Pilot data suggest that Fgf receptor 2 (Fgfr2) during embryogenesis increases the number of "intermediate" progenitors in the SVZ, which in turn is associated with pyramidal neuron genesis in PFC. In contrast, Fgf receptor1 (Fgfr1) is not involved in prenatal cortical development, but may increase the differentiation or survival of cortical parvalbumin+ and somatostatin+ inhibitory interneurons by an action in postnatal glial cells. In this competing continuation proposal, we hypothesize that Fgfr2 signaling in embryogenesis expands the surface area of PFC by stimulating the production of intermediate progenitors in the SVZ from radial glial cells. This will be tested in Specific Aim 1 by tracing the progeny of radial glial cells harboring a deletion of Fgfr2 alleles induced at specific stages of prenatal development. Also, general cortical morphogenesis will be compared amongst mice lacking Fgfr2 versus mice with a combined deletion of Fgfr1, Fgf2 and Fgf3. The effect of Fgf receptor stimulation and blockade upon identified radial glial cells will be also assessed by electroporating dominant negative and dominant active Fgf receptors driven by a specific radial glial promoter. In specific aim 2 and 3, we will assess whether Fgf signaling in glial cells indirectly promotes the survival or functional maturation of cortical inhibitory neurons expressing Parvalbumin (PV) and Somatostatin (ST) and the developmental time window for this action. In Aim 2, we will transplant GFP+ wild type interneurons into the postnatal cortex of Fgfr1 mutant mice to determine whether the Fgfr1 mutant cortex is less permissive for interneuron maturation. We will also assess intrinsic firing properties and synaptic integration into the cortical network of the transplanted and endogenous interneurons in Fgfr1 mutant mice. In specific aim 3, we will specifically inactivate Fgfr1 in GFAP+ cells by virus-induced or temporally regulated recombination of Fgfr1 at either prenatal or postnatal stages of development, and examine interneuron maturation and survival. Together, the experiments will elucidate how specific Fgf receptors may play specific roles in different epochs of life. PUBLIC HEALTH RELEVANCE Abnormalities in the development of the prefrontal cortex are thought to underlie the symptoms of schizophrenia, autism, attention deficit hyperactivity and drug addiction. This proposal investigates how growth factors of the FGF family establish the primary structure of the cerebral cortex by controlling the genesis of cortical projection neurons from SVZ precursors. The project also focuses on the role of glia in the maturation of inhibitory interneurons during postnatal development of the cerebral cortex. Both aspects may offer promising leads to correct or reverse the excitatory and inhibitory neuron imbalances that are present in the cerebral cortex of neuropsychiatric and impulse control disorders.