Convergent Synaptic Mechanisms in Neurodevelopmental Disorders

神经发育障碍中的趋同突触机制

• 批准号: 8720089
• 负责人: Jacqueline N Crawley
• 金额: $ 56.62万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720089
• 关键词: Actins; Acute; Address; Angelman Syndrome; Behavioral; Biological; Biological Markers; Brain-Derived Neurotrophic Factor; Chemosensitization; Chronic; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Cytoskeleton; Data; Defect; Dendritic Spines; Discrimination; Disease; Down Syndrome; Economics; Elements; Emotional; Etiology; Event; Exhibits; F-Actin; Failure; Family; Financial cost; Fragile X Syndrome; Frequencies; Functional disorder; Gene Expression; Gene Mutation; Genetic; Guanosine Triphosphate Phosphohydrolases; Healthcare Systems; Hippocampus (Brain); Human; Impaired cognition; Impairment; Intellectual functioning disability; Intervention; Investigation; Knockout Mice; Learning; Learning Disabilities; Ligands; Location; Long-Term Potentiation; Mediating; Medical; Memory; Modeling; Modification; Molecular; Molecular Abnormality; Monomeric GTP-Binding Proteins; Mus; Mutant Strains Mice; Neurobiology; Neurodevelopmental Disorder; Neurons; Pathway interactions; Performance; Pharmaceutical Preparations; Phosphotransferases; Physiologic pulse; Physiological; Prefrontal Cortex; Principal Investigator; Rattus; Recovery; Regimen; Regulation; Rett Syndrome; Rodent; Rodent Model; Signal Transduction; Slice; Synapses; Synaptic plasticity; Syndrome; Testing; Therapeutic; Time; Training; Treatment Protocols; Water; cognitive function; cognitive training; conditioning; disability; efficacy testing; improved; innovation; mimetics; mouse Ts65Dn; mouse model; multidisciplinary; mutant; mutant mouse model; novel; preclinical evaluation; public health relevance; touchscreen; visual learning

DESCRIPTION (provided by applicant): Diverse genetic mutations cause different neurodevelopmental disorders, yet many syndromes share similar intellectual impairments. The overarching aim of this multidisciplinary project, enabled by specific expertise from three principal investigators, is to discover fundamental mechanisms responsible for cognitive impairments across genetic mouse models of diverse neurodevelopmental disorders. We hypothesize that various upstream genetic abnormalities converge on common downstream mechanisms to produce learning disabilities across syndromes. Synaptic activation of small GTPases drives remodeling of the dendritic spine actin cytoskeleton, a far-downstream mechanism which underlies enduring synaptic plasticity, learning and memory. We will test the hypothesis that failure to properly reorganize the subsynaptic cytoskeleton is a shared endpoint across neurodevelopmental disorders, employing established mouse models of Fragile X (Fmr1), Rett (Mecp2), Down (Ts65Dn) and Angelman (Ube3a) syndromes. Aim 1 will use theta burst stimulation and three learning paradigms to test the hypothesis that the four mutant lines all exhibit deficits in synaptic GTPase activation and actin remodeling in cortex and hippocampus. We further propose that normalizing these signaling dysfunctions will restore cognitive functions. Our preliminary data indicate that changing the spacing of afferent activity rescues hippocampal long-term potentiation (LTP), and changing the spacing of cognitive training rescues one form of learning. Aim 2 will test the hypotheses that newly identified timing rules for LTP will engage the impaired actin regulatory cascades and facilitate synaptic potentiation in the mutants, and that analogous spaced training regimens in three different cognitive tasks will restore synaptic GTPase activation and learning. We discovered that impairments in actin regulation, LTP and learning in Fmr1 and Ube3a mice are rescued by increasing the availability of BDNF, which facilitates signaling to restore actin stabilization. Ai 3 will employ these same downstream endpoints for preclinical evaluation of pharmacological rescues. Two compounds that lower the threshold for GTPase activation in the wildtypes will be tested for efficacy in (1) reversing defects in signaling leading to actin stabilization, (2) restoing LTP, and (3) improving cognitive performance in the four models. Investigations of novel, broad spectrum behavioral and pharmacological interventions which enhance the activation of downstream mechanisms, and which can be readily implemented clinically, will address a fundamental neurobiological hypothesis with unifying translational implications for improving cognitive abilities in multiple neurodevelopmental disorders.

描述（由申请人提供）：不同的基因突变导致不同的神经发育障碍，但许多综合征具有相似的智力障碍。这个多学科项目的总体目标是，通过三位主要研究人员的特定专业知识，发现各种神经发育障碍遗传小鼠模型中认知障碍的基本机制。我们假设，各种上游遗传异常汇聚在共同的下游机制，以产生学习障碍的综合征。小GTP酶的突触激活驱动树突棘肌动蛋白细胞骨架的重塑，这是持久的突触可塑性、学习和记忆的基础的远下游机制。我们将使用已建立的脆性X（Fmr1）、Rett（Mecp2）、Down（Ts65Dn）和Angelman（Ube3a）综合征小鼠模型，检验未能正确重组突触下细胞骨架是神经发育障碍的共同终点这一假设。目的1将使用theta爆发刺激和三种学习范式来检验这四种突变系都表现出皮层和海马中突触GT3激活和肌动蛋白重塑的缺陷的假设。我们进一步提出，使这些信号功能障碍正常化将恢复认知功能。我们的初步数据表明，改变传入活动的间隔拯救海马长时程增强（LTP），改变认知训练的间隔拯救一种学习形式。目的2将测试的假设，新确定的定时规则LTP将从事受损的肌动蛋白调节级联和促进突触增强的突变体，并在三个不同的认知任务类似的间隔训练方案将恢复突触GT3激活和学习。我们发现，在Fmr1和Ube3a小鼠中，肌动蛋白调节、LTP和学习的损伤通过增加BDNF的可用性来挽救，BDNF促进信号传导以恢复肌动蛋白稳定。Ai 3将采用这些相同的下游终点进行药物补救的临床前评价。将测试两种降低野生型中GT α活化阈值的化合物在以下方面的功效：（1）逆转导致肌动蛋白稳定化的信号传导缺陷，（2）恢复LTP，和（3）改善四种模型中的认知表现。研究新的、广谱的行为和药理干预措施，增强下游机制的激活，并且可以很容易地在临床上实施，将解决一个基本的神经生物学假设，具有统一的翻译意义，用于改善多种神经发育障碍的认知能力。