Convergent Synaptic Mechanisms in Neurodevelopmental Disorders

神经发育障碍中的趋同突触机制

• 批准号: 8630831
• 负责人: Jacqueline N Crawley
• 金额: $ 58.66万
• 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/8630831
• 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

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. Aim 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) restoring 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.

不同的基因突变导致不同的神经发育障碍，但也有许多综合征 具有相似的智力障碍。这个多学科项目的总体目标是 由三位主要研究人员的具体专业知识推动，是为了发现根本性的 不同遗传小鼠模型认知障碍的机制 神经发育障碍。我们假设各种上游遗传异常 集中在共同的下游机制上以产生学习障碍 综合症。小 GTP 酶的突触激活驱动树突棘肌动蛋白的重塑 细胞骨架，一种远下游机制，是持久突触可塑性的基础， 学习和记忆。我们将检验以下假设：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，利用 建立了 Fragile X (Fmr1)、Rett (Mecp2)、Down (Ts65Dn) 和 Angelman 小鼠模型 (Ube3a) 综合征。目标1将使用theta爆发刺激和三种学习范式来测试 四个突变株系均表现出突触 GTP 酶激活缺陷的假设 皮质和海马体的肌动蛋白重塑。我们进一步建议使这些 信号传导功能障碍将恢复认知功能。我们的初步数据表明 改变传入活动的间隔可挽救海马长时程增强（LTP），以及 改变认知训练的间隔可以挽救一种学习形式。目标 2 将测试 假设新确定的 LTP 时间规则将涉及受损的肌动蛋白调节 级联并促进突变体中的突触增强，以及类似的间隔训练 三种不同认知任务中的治疗方案将恢复突触 GTP 酶的激活和学习。 我们发现 Fmr1 和 Ube3a 小鼠的肌动蛋白调节、LTP 和学习能力受损 通过增加 BDNF 的可用性来拯救，BDNF 有助于恢复肌动蛋白的信号传导 稳定。目标 3 将采用这些相同的下游终点来进行临床前评估 药物救援。两种可降低 GTP 酶激活阈值的化合物 将测试野生型在以下方面的功效：(1) 逆转导致肌动蛋白的信号传导缺陷 稳定，(2) 恢复 LTP，(3) 提高四种模型的认知表现。 对新颖、广谱的行为和药物干预措施的研究 增强下游机制的激活，且易于实施 在临床上，将通过统一翻译来解决基本的神经生物学假设 对改善多种神经发育障碍的认知能力的影响。