Regulation of 22q11 Genes in Embryonic and Adult Forebrain

 描述（由申请人提供）：导致自闭症谱系障碍（ASD）、注意力缺陷多动障碍（ADHD）、精神分裂症（SCZ）和其他皮质回路发育（DCCD）疾病中大脑皮层关联区域之间连接不足、连接过度和连接错误的发育机制尚未确定。我们在该项目最后阶段发表的工作，加上额外的初步数据，表明不同的皮质发育机制在DiGeorge/22q11.2缺失综合征（22 q11 DS）的小鼠遗传模型中被破坏，这是一种与ASD，ADHD和SCZ脆弱性最强相关的遗传综合征。我们现在将测试的假设，选择性的，可逆的发展中断的连接层2/3皮质投射神经元之间和联合皮质内的基础行为变化的小鼠模型22 q11缺失综合征（22 q11 DS）。我们将首次定义在ASD、ADHD和SCZ脆弱性的遗传模型中，联合皮质中选择性改变的发育与神经发生、神经元分化、连接和行为的病理变化之间的关系。在具体目标1中，我们将确定是否改变基础祖细胞增殖选择性减少2/3层皮质投射神经元（cPN）的频率在22 q11 DS小鼠模型的关联区域。我们将评估轴突生长的变化，并从减少的2/3层cPN的数量和质量的变化，在联合皮质连接的指导。我们的数据将确定是否减少层2/3 cPN神经发生和轴突生长的相关中断帐户22 q11 DS行为病理由于“连接不足”。在具体目标2中，我们将确定2/3层cPN树突分化中代谢介导的变化是否会破坏2/3层cPN与关联皮质区中关键抑制或调节输入之间的局部突触接触的发育。我们将评估这些变化的贡献，显然是由不同的22 q11候选基因的影响，独立于减少层2/3 cPN的发生，在22 q11 DS小鼠模型的关键行为障碍。在具体目标3中，我们将评估通过药理学操纵抗氧化防御/活性氧清除在发育期与成年期逆转这些发育变化的可行性。我们目前的观察表明，22 q11缺失导致氧化应激和皮质神经元生长减少，抗氧化剂N-乙酰半胱氨酸可以逆转这些影响。我们的工作将提供一个机制的基础，目前的努力，使用抗氧化剂作为一种治疗剂的患者与广泛的DCCD。我们的研究结果将共同定义发展机制的选择性贡献，导致ASD，ADHD或SCZ中的关联皮层过度/欠连接与错误连接，以及纠正特定发育缺陷以改善DCCD行为结果的相对有效性。

 DESCRIPTION (provided by applicant): The developmental mechanisms that lead to under-connectivity, over-connectivity, and mis-connectivity between association regions of the cerebral cortex in autistic spectrum disorder (ASD), attention deficit- hyperactivity disorder (ADHD), schizophrenia (SCZ) and other diseases of cortical circuit development (DCCDs) remain undefined. Our published work from the last phase of this project, plus additional preliminary data, indicates that distinct cortical developmental mechanisms are disrupted in mouse genetic models of DiGeorge/22q11.2 Deletion Syndrome (22q11DS), a genetic syndrome with one of the strongest associations with ASD, ADHD and SCZ vulnerability. We will now test the hypothesis that selective, reversible developmental disruption of connections made by layer 2/3 cortical projection neurons between and within association cortices underlies behavioral changes in mouse models of 22q11 Deletion Syndrome (22q11DS). We will define for the first time the relationship between selectively altered development in association cortices and pathologic changes in neurogenesis, neuronal differentiation, connectivity and behavior in genetic models of ASD, ADHD, and SCZ vulnerability. In Specific Aim 1, we will determine whether altered basal progenitor proliferation selectively diminishes of layer 2/3 cortical projection neuron (cPN) frequency in association regions in 22q11DS mouse models. We will evaluate changes in axon growth and guidance from the diminished population of layer 2/3 cPNs for quantitative and qualitative changes in association cortical connectivity. Our data will establish whether reduced layer 2/3 cPN neurogenesis and related disruption of axon growth account for 22q11DS behavioral pathology due to "under-connectivity". In Specific Aim 2, we will determine whether metabolically-mediated changes in layer 2/3 cPN dendritic differentiation disrupt development of local synaptic contacts between layer 2/3 cPNs and key inhibitory or modulatory inputs in association cortical areas. We will assess the contribution of these changes, apparently influenced by distinct 22q11 candidate genes, independent of diminished layer 2/3 cPN genesis to key behavioral impairments in 22q11DS mouse models. In Specific Aim 3, we will assess the feasibility of reversing these developmental changes via pharmacological manipulation of antioxidant defense/reactive oxygen species clearance during development versus adulthood. Our current observations suggest that 22q11 deletion results in oxidative stress and diminished growth in cortical neurons, and that the anti-oxidant N-acetyl cysteine can reverse these effects. Our work will provide a mechanistic foundation for current efforts to use antioxidants as a therapeutic agent for patients with a wide range of DCCDs. Together our results will define the selective contribution of developmental mechanisms that lead to association cortical over/under connectivity versus misconnectivity in ASD, ADHD or SCZ, and the relatively effectiveness of correcting specific developmental deficits for improving behavioral outcomes in DCCDs.