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:
- 金额:$ 58.66万
- 依托单位:
- 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:
- 关键词:ActinsAcuteAddressAngelman SyndromeBehavioralBiologicalBiological MarkersBrain-Derived Neurotrophic FactorChemosensitizationChronicClinicalClinical TrialsCognitiveCognitive deficitsCytoskeletonDataDefectDendritic SpinesDiscriminationDiseaseDown SyndromeEconomicsElementsEmotionalEtiologyEventExhibitsF-ActinFailureFamilyFinancial costFragile X SyndromeFrequenciesFunctional disorderGene ExpressionGene MutationGeneticGuanosine Triphosphate PhosphohydrolasesHealthcare SystemsHippocampus (Brain)HumanImpaired cognitionImpairmentIntellectual functioning disabilityInterventionInvestigationKnockout MiceLearningLearning DisabilitiesLigandsLocationLong-Term PotentiationMediatingMedicalMemoryModelingModificationMolecularMolecular AbnormalityMonomeric GTP-Binding ProteinsMusMutant Strains MiceNeurobiologyNeurodevelopmental DisorderNeuronsPathway interactionsPerformancePharmaceutical PreparationsPhosphotransferasesPhysiologic pulsePhysiologicalPrefrontal CortexPrincipal InvestigatorRattusRecoveryRegimenRegulationRett SyndromeRodentRodent ModelSignal TransductionSliceSynapsesSynaptic plasticitySyndromeTestingTherapeuticTimeTrainingTreatment ProtocolsWatercognitive functioncognitive trainingconditioningdisabilityefficacy testingimprovedinnovationmimeticsmouse Ts65Dnmouse modelmultidisciplinarymutantmutant mouse modelnovelpreclinical evaluationpublic health relevancetouchscreenvisual 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
项目成果
期刊论文数量(0)
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Jacqueline N Crawley其他文献
Mainstreaming Mice
将小鼠纳入主流
- DOI:
10.1038/npp.2011.168 - 发表时间:
2011-12-13 - 期刊:
- 影响因子:7.100
- 作者:
Brooke A Babineau;Mu Yang;Jacqueline N Crawley - 通讯作者:
Jacqueline N Crawley
Jacqueline N Crawley的其他文献
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{{ truncateString('Jacqueline N Crawley', 18)}}的其他基金
Convergent Synaptic Mechanisms in Neurodevelopmental Disorders
神经发育障碍中的趋同突触机制
- 批准号:
8720089 - 财政年份:2013
- 资助金额:
$ 58.66万 - 项目类别:
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