Probing circuit assembly errors in a monogenic model of comorbid brain disorders

 描述(由申请人提供)：本次修订的竞争更新的重点是了解将单基因突变与认知缺陷联系起来的神经生物学底物。目前，还没有有效的治疗方法来治疗定义神经发育障碍(NDDS)的认知障碍。为了制定改善受影响个人生活的治疗策略，必须了解认知和行为适应能力降低的神经生物学基础在这些疾病中是如何受损的。我们在上一个预算期间的工作建立了Syngap1杂合子KO小鼠作为一个健壮的模型，它将促进我们对NDD中认知和行为中断是如何产生的理解。特别是，我们证实了致病的Syngap1突变通过改变前脑兴奋性神经元的成熟率来损害发育中的大脑。我们还成功地将Syngap1突变小鼠的前脑锥体神经元成熟与认知能力下降联系起来。然而，目前尚不清楚神经元成熟变化实际上是如何降低认知能力的。我们在这个修订的建议中的研究旨在探索这样的假设，即在Syngap1突变体中存在电路组装错误的空间模式。我们认为，前脑锥体神经元的交替成熟破坏了构成认知能力的皮质回路的组装，认知能力被假设为将致病的Syngap1突变与认知改变联系起来的关键神经生物学底物。我们预期结果的影响是，电路组装错误的模式可以定义Syngap1突变小鼠所显示的特定认知内表型，这将为揭示单个基因中断导致认知障碍的病因提供重要的见解。此外，Syngap1突变体中组装错误的模式可以作为比较基准，以了解其他单基因形式的NDDS改变电路模式的相似和/或差异。这项提议的长期目标是确定大脑中受致病性Syngap1突变影响最严重的细胞。一旦我们了解了这种疾病的细胞起源，我们就会有一个更好的切入点来洞察TE分子的扰动，这些扰动会触发系统水平的功能障碍，从而直接导致认知能力下降。在下一个要求的预算期结束时，我们相信我们将把这种疾病减少到相对选择性的神经元池，这些神经元对致病的Syngap1突变特别敏感。当这些信息与在前一个预算期发现的关键期信息相结合时，我们将拥有理想的切入点来评估致病的Synagp1突变如何扰乱控制发育中的前脑锥体神经元生长和成熟的分子通路。在接下来的预算期间，我们将开始研究发育中Syngap1在这一神经元池中的表达变化如何触发神经元成熟的变化。

 DESCRIPTION (provided by applicant): The focus of this revised competitive renewal is to understand the neurobiological substrates that link single gene mutations to cognitive deficits. Currently, there is no effective treatment for the cognitive disruptions that define neurodevelopmental disorders (NDDs). In order to develop therapeutic strategies that improve the lives of affected individuals, it is imperative to understand how the neurobiological substrates that underlie reduced cognition and behavioral adaptations are damaged in these disorders. Our work during the last budget period established Syngap1 Heterozygous KO mice as a robust model that will advance our understanding of how cognitive and behavioral disruptions arise in NDDs. In particular, we established that pathogenic Syngap1 mutations damage the developing brain by altering the maturation rate of forebrain excitatory neurons. We also succeeded in connecting alterations to forebrain pyramidal neuron maturation in Syngap1 mutant mice to reduced cognitive ability. However, it remains unclear how altered neuronal maturation actually degrades cognitive ability. Our studies in this revised proposal are designed to explore the hypothesis that there is a spatial pattern of circuit assembly errors in Syngap1 mutants. We believe that alternated maturation of forebrain pyramidal neurons disrupts the assembly of cortical circuits that underlies cognitive ability, which is hypothesized to be a key neurobiological substrate that connects pathogenic Syngap1 mutations to altered cognition. The impact of our expected results is that the pattern of circuit assembly errors could define the particular cognitive endophenotype displayed by Syngap1 mutant mice, which would provide significant insight into the etiology of reduced cognition due to a single gene disruption. In addition, the patterns of assembly errors in Syngap1 mutants could be used as a comparative benchmark to understand similarities and/or differences in patterns of altered circuitry in other monogenic forms of NDDs. The long-term goal of this proposal is to identify the cells in the brain that are most severely impacted by pathogenic Syngap1 mutations. Once we understand the cellular origins of the disorder, we will have a much better entry point for gaining insight into te molecular perturbations that trigger the systems level dysfunction that directly leads to reduced cognitive ability. At the conclusion of the next requested budget period, we believe we will have reduced this disorder down to a relatively selective pool of neurons that are particularly sensitiv to pathogenic Syngap1 mutations. When this information is combined with the critical period information discovered in the previous budget period, we will have the ideal entry point for assessing how pathogenic Synagp1 mutations disrupt the molecular pathways that control growth and maturation of developing forebrain pyramidal neurons. In the subsequent budget period, we would then begin studying how altered developmental Syngap1 expression in this pool of neurons triggers changes in neuronal maturation.