Hippocampal synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition

海马突触和回路机制介导 Dyrk1a 在社会认知中的功能

• 批准号: 10562383
• 负责人: Amar Sahay
• 金额: $ 60.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562383
• 关键词: Acute; Adult; Affect; Behavior; Biological Process; Brain; Cells; Child; Chronic; Complement; Data; Development; Disease; Disease model; Down-Regulation; Electrophysiology (science); Enhancers; Exhibits; Genes; Genetic; Genetic Epistasis; Genetic study; Hippocampal Mossy Fibers; Hippocampus; Impaired cognition; Impairment; Learning; Mediating; Memory; Memory impairment; Modeling; Molecular; Molecular Target; Mus; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Parvalbumins; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Risk; Role; Seizures; Social Behavior; Specificity; Synapses; System; Testing; Tyrosine Phosphorylation; United States; Viral; autism spectrum disorder; cell type; dentate gyrus; exome sequencing; experience; gene therapy; granule cell; in vivo; inhibitory neuron; loss of function; loss of function mutation; memory recognition; mimetics; mossy fiber; mouse model; mutant; optogenetics; patch clamp; recruit; repetitive behavior; social; social cognition

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.

项目总结/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 已经确定了双特异性中的单倍不足功能丧失（LOF）突变， ASD综合征中酪氨酸磷酸化调节激酶Dyrk 1a基因的研究但 半合子Dyrk 1a LOF对突触和回路机制的功能影响 社会认知仍然知之甚少。这一挑战被放大，因为Dyrk 1a 磷酸化>70个底物，Dyrk 1a LOF可能会破坏许多生物过程 在发展过程中。目前，还没有药物可以增强或恢复Dyrk 1a的功能。 总之，这些观察结果强调了识别细胞类型和特定电路的必要性。 机制，可能有针对性地逆转Dyrk 1a相关的社会认知障碍。这 一项提案试图通过识别Dyrk 1a依赖的突触和回路来弥合这些差距 调节社会认可的机制，可以在成年后逆转 Dyrk 1a相关的社会认知电路和行为障碍的发展损失。 所提出的目的将建立在我们对Dyrk 1a和Dyrk 1b的体内功能遗传上位性分析的基础上。 它的底物之一，Ablim 3，在海马苔藓纤维，以测试这一途径的作用， 成年Dyrk 1a半合子小鼠的逆转回路和社会识别记忆障碍 在ASD中模拟Dyrk 1a单倍不足。目标的执行具有指导潜力 靶向Dyrk 1a、Ablim 3和 小清蛋白抑制性神经元介导GABA能抑制，在成人脑中为“Dyrk 1a 增强剂”来挽救Dyrk 1a导致的ASD中的社会认知障碍 单倍不足