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

基本信息

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
项目类别：
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

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

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项目摘要

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，在美国影响54名儿童中的1个，其特征是社会认知受损，重复行为和癫痫发作风险。遗传研究和大规模的外显局努力已经确定了双重特异性中的单倍体功能丧失（LOF）突变综合症ASD中的酪氨酸 - 磷酸化调节的激酶DyRK1A基因。但是，半合子dyrk1a lof对突触和电路机制的功能影响社会认知仍然知之甚少。由于dyrk1a，这一挑战被放大了磷酸化> 70个底物和Dyrk1a LOF可能会破坏许多生物学过程在开发过程中。当前，没有药物可以增强或恢复DYRK1A功能。这些观察结果共同强调了识别细胞类型和电路特异性的需求可能旨在逆转DYRK1A相关的社会认知障碍的机制。这提案旨在通过识别DYRK1A依赖性突触和电路来弥合这些差距介导社会认可的机制，可以在成年后逆转社会认知电路和行为中与DYRK1A相关的损害的发展丧失。拟议的目标将基于我们对Dyrk1a和其海马苔藓纤维中的底物之一Ablim3，以测试该途径在成人dyrk1a半合子小鼠的逆转电路和社会识别记忆障碍那对ASD中的DYRK1A单倍体弥补进行了建模。执行目标的潜力针对Dyrk1a，Ablim3和白蛋白抑制性神经元介导的GABA能抑制作用，成年大脑为“ Dyrk1a 增强剂”，以挽救DYRK1A产生的ASD社会认知障碍单倍不足。