Regulation of 22q11 Genes in Embryonic and Adult Forebrain

 描述(申请人提供)：在自闭症谱系障碍(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疾病(DCCDs)中，导致大脑皮层相关区域之间连接不足、过度连接和错误连接的发育机制仍未确定。我们发表的该项目最后阶段的工作，加上更多的初步数据，表明DiGeorge/22q11.2缺失综合征(22q11DS)的小鼠遗传模型中不同的皮质发育机制受到干扰，这是一种与ASD、ADHD和SCZ易损性最相关的遗传综合征。我们现在将测试这一假设，即22q11缺失综合征(22q11DS)小鼠模型的行为变化是由第2/3层皮质投射神经元在联合皮质之间和内部建立的选择性、可逆的发育中断造成的。我们将首次在ASD、ADHD和SCZ易损性的遗传模型中确定选择性联合皮质发育改变与神经发生、神经元分化、连接和行为的病理变化之间的关系。在特定的目标1中，我们将确定在22q11DS小鼠模型中，改变的基底祖细胞增殖是否选择性地降低了关联区第2/3层皮质投射神经元(CPN)的频率。我们将评估轴突生长的变化，并从2/3层CPN数量减少的群体中引导相关皮质连接性的数量和质量变化。我们的数据将确定是否第2/3层CPN神经发生减少和相关的轴突生长中断是22q11DS由于连接不足而导致的行为病理。在具体目标2中，我们将确定代谢介导的第2/3层CPN树突分化的变化是否扰乱了第2/3层CPN与相关皮质区域关键的抑制性或调节性输入之间局部突触联系的发展。我们将评估这些明显受不同的22q11候选基因影响的变化对22q11DS小鼠模型中关键行为障碍的贡献，这些变化与第2/3层CPN发生的减少无关。在具体目标3中，我们将评估在发育阶段与成年期相比，通过药物操作抗氧化防御/活性氧清除来逆转这些发育变化的可行性。我们目前的观察表明，22q11缺失导致皮质神经元氧化应激和生长减弱，抗氧化剂N-乙酰半胱氨酸可以逆转这些影响。我们的工作将为目前使用抗氧化剂作为治疗各种DCCDs患者的药物提供机制基础。综上所述，我们的结果将定义在ASD、ADHD或SCZ中导致连接过度/连接不足与连接不良相关的发育机制的选择性贡献，以及纠正特定发育缺陷对改善DCCDs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.