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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：
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
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/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

项目摘要

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