Hippocampal synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition

项目摘要/摘要 自闭症谱系障碍(ASD)是一类异质性神经发育障碍， 在美国，每54名儿童中就有1名受到影响，其特征是社会认知受损， 重复行为和癫痫发作风险。基因研究和大规模外显子组测序工作 已经在双重特异性中发现了单基因不足的功能丧失(LOF)突变 综合征型ASD患者酪氨酸磷酸化调节激酶Dyrk1a基因的研究然而， 半合子Dyrk1a LOF对突触和环路机制的功能影响 人们对社会认知仍然知之甚少。这一挑战被放大是因为Dyrk1a 磷酸化底物和Dyrk1a LOF可能扰乱许多生物过程 在开发过程中。目前，还没有增强或恢复Dyrk1a功能的药物。 总之，这些观察结果强调了识别特定细胞类型和特定电路的必要性 这些机制可能旨在逆转Dyrk1a相关的社会认知障碍。这 一项提案试图通过识别Dyrk1a依赖的突触和回路来弥合这些差距 调节社会认同的机制，可以在成年后有针对性地逆转 社会认知回路和行为中Dyrk1a相关损害的发育性丧失。 拟议的目标将建立在我们对Dyrk1a和Dyrk1a的体内功能遗传上位性分析的基础上。 它的底物之一，Ablim3，在海马苔藓纤维中，测试这一途径在 成年Dyrk1a半合子小鼠的翻转回路和社会再认记忆损害 这是ASD中Dyrk1a单倍体功能不全的模型。AIMS的执行具有指导作用的潜力 针对Dyrk1a、Ablim3和Dyrk1a分子和电路底物的基因治疗策略 小白蛋白抑制神经元介导的GABA能抑制，在成人脑中称为“Dyrk1a” “增强剂”挽救由Dyrk1a引起的ASD患者的社会认知障碍 单倍体功能不全。

Project Summary/Abstract Autism spectrum disorder (ASD) is a class of heterogeneous neurodevelopmental disorders that affects 1 in 54 children in the United States and is characterized by impaired social cognition, repetitive behaviors and seizure risk. Genetic studies and large-scale exome-sequencing efforts have identified haplo-insufficient loss of function (LOF) mutations in the Dual specificity tyrosine-phosphorylation-regulated kinase Dyrk1a gene in syndromic ASD. However, the functional impact of hemizygous Dyrk1a LOF on synaptic and circuit mechanisms underlying social cognition remain poorly understood. This challenge is magnified because Dyrk1a phosphorylates >70 substrates and Dyrk1a LOF is likely to disrupt many biological processes during development. Currently, there are no drugs that enhance or restore Dyrk1a function. Together, these observations underscore the need to identify cell-type and circuit-specific mechanisms that maybe targeted to reverse Dyrk1a associated social cognition impairments. This proposal seeks to bridge these gaps by identifying a Dyrk1a-dependent synaptic and circuit mechanism mediating social recognition that can be targeted in adulthood to reverse developmental loss of Dyrk1a-associated impairments in social cognition circuitry and behavior. The proposed Aims will build on our in vivo functional genetic epistasis analysis of Dyrk1a and one of its substrates, Ablim3, in hippocampal mossy fibers to test the role of this pathway in reversing circuit and social recognition memory impairments in adult Dyrk1a hemizygous mice that models Dyrk1a haploinsufficiency in ASD. Execution of the Aims harbors potential to guide gene therapy strategies targeting molecular and circuit substrates of Dyrk1a, Ablim3 and parvalbumin inhibitory neuron mediated GABAergic inhibition, in the adult brain as “Dyrk1a enhancers” to rescue social cognition impairments in ASD resulting from Dyrk1a haploinsufficiency.