Convergent Synaptic Mechanisms in Neurodevelopmental Disorders

神经发育障碍中的趋同突触机制

基本信息

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
项目类别：
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

项目摘要

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）：不同的遗传突变会引起不同的神经发育障碍，但许多综合症具有相似的智力障碍。由三位主要研究人员的特定专业知识启用的这个多学科项目的总体目的是发现负责各种神经发育障碍遗传小鼠模型的认知障碍的基本机制。我们假设各种上游遗传异常在常见的下游机制上汇聚，以产生跨综合症的学习障碍。小型GTP酶的突触激活驱动树突状脊柱肌动蛋白细胞骨架的重塑，这是一种远下的机制，其基础是持久的突触可塑性，学习和记忆。我们将检验以下假设：未能正确重新组织突触次骨骼骨骼是神经发育障碍之间的共享终点，该终点是采用脆弱X（FMR1），RETT（MECP2），RETT（MECP2），DOSS（TS65DN）和Angelman（ube3a）综合征的已建立的小鼠模型。 AIM 1将使用theta爆发刺激和三个学习范例来检验以下假设：四个突变线均在突触GTPase激活中表现出缺陷和皮质和海马中的肌动蛋白重塑。我们进一步建议使这些信号传导功能障碍归一化将恢复认知功能。我们的初步数据表明，改变传入活动的间距可以挽救海马长期增强（LTP），并改变认知训练的间距挽救了一种学习形式。 AIM 2将测试新确定的LTP时序规则的假设将使肌动蛋白调节级联反应受损，并促进突变体的突触增强，并且在三种不同的认知任务中类似的间隔训练方案将恢复突触的GTPase激活和学习。我们发现，通过增加BDNF的可用性来挽救肌动蛋白调节，LTP和学习中的障碍，并促进了信号传导以恢复肌动蛋白稳定的稳定。 AI 3将采用这些相同的下游端点来对药理学救援进行临床前评估。降低野生型GTPase激活阈值的两种化合物将在（1）逆转信号传导中的缺陷中进行测试，从而导致肌动蛋白稳定性，（2）重新载入LTP，以及（3）在四个模型中提高认知性能。对新的，广泛的行为和药理干预措施的研究，这些干预措施增强了下游机制的激活，并且可以在临床上很容易实施，这将解决一种基本的神经生物学假说，具有统一的转化影响，以提高多种神经产生疾病的认知能力。