The Pathophysiological Role of Cerebellar Glia in Rett Syndrome
小脑胶质细胞在 Rett 综合征中的病理生理学作用
基本信息
- 批准号:10183494
- 负责人:
- 金额:$ 39.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AMPA ReceptorsAgonistAstrocytesBehaviorBehavior assessmentBehavioralBiological AssayBrainBrain DiseasesCell physiologyCell surfaceCellsCerebellar DiseasesCerebellumComplexConfocal MicroscopyDataDopamineDopamine D1 ReceptorEtiologyExtracellular DomainFiberFunctional disorderGenetic TranscriptionGlutamatesGreen Fluorescent ProteinsHandHand functionsHeadHomeostasisImageImpairmentIndividualInferiorInfusion proceduresKnockout MiceKnowledgeLightLong-Term PotentiationMachine LearningMedulla oblongata oliveMembraneMembrane PotentialsMethyl-CpG-Binding Protein 2MolecularMotorMovementMusMutationNeurogliaNeurologic SymptomsNeuronsOpsinPHluorinPathologicPermeabilityPharmacologyPhotometryPlayPropertyPurkinje CellsResearch PersonnelResolutionRestRett SyndromeRodent ModelRoleSliceSocial BehaviorSpeechSpeedSurfaceSymptomsSynapsesSynaptic TransmissionSynaptic plasticityTestingTimeVariantWhole-Cell RecordingsWomanautism spectrum disorderbiophysical propertiesconditional knockoutex vivo imagingextracellulargirlsimprovedin vivoloss of function mutationmotor behaviormotor deficitoptogeneticsrelating to nervous systemsensorsevere intellectual disabilitysocialsocial deficitstraffickinguptake
项目摘要
PROJECT SUMMARY/ABSTRACT
Rett syndrome (RTT) is the leading cause of severe intellectual disability in girls and women. Individuals with
RTT develop typically until 6-18 months, when autism-like behaviors and deficits in purposeful hand use and
speech start to develop. Loss-of-function mutations in the transcriptional regulator methyl-CpG-binding protein
2 (MECP2) occur in >95% of RTT cases. Initially, researchers regarded MeCP2 deficiency in neurons as the
exclusive cause of RTT. However, recent studies have revealed that glia have a pathological role in RTT
etiology. Studies have not yet uncovered the underlying cellular mechanisms of glial cell dysfunction in Mecp2
rodent models or the impact of this dysfunction on brain function. In this study, we propose to examine the
contribution of a specific glial subtype, Bergmann glia cells (BGs) in the cerebellum, to the motor and social
deficits in RTT. We will focus on BGs because (1) cerebellar disruption likely contributes to the motor and
social deficits in RTT and (2) BGs are the major glial subtype in the cerebellum. We propose to characterize
cerebellar function in conditional knockout (cKO) mice that lack Mecp2 in BGs using a repertoire of
approaches, including intracellular whole-cell recordings, in vivo recordings of single units and local field
potentials, in vivo and ex vivo imaging of genetically-encoded Ca2+, glutamate, and dopamine (DA) sensors
(GCaMP7, iGluSnFr, and dLight1.1, respectively), optogenetics, chemogenetics, near super-resolution
confocal microscopy, and behavioral assessments using unbiased machine-learning approaches. Our
preliminary results indicate deficits in BGs from Mecp2-deficient mice, including higher expression levels of the
GluA1 subunit of AMPA receptors (AMPARs), and depolarized membrane potentials. In addition, we have
preliminary evidence of DAergic modulation of BGs through the activation of D1 receptors (D1Rs) activated by
either electrical or optogenetic stimulation of DAergic inputs to the cerebellum. Of high relevance to motor and
social symptoms in RTT, the expression levels of D1Rs, which modulate GluA1 surface insertion, are higher in
Mecp2 KO mice. We hypothesize that BGs in the cerebellum have a pathophysiological role in motor and
social deficits in Mecp2-deficient mice. We propose two Aims: (1) Define cerebellar BG dysfunction in Mecp2
cKO mice;; (2) Characterize DAergic modulation of cerebellar BGs in Mecp2 cKO mice. The proposed studies
will elucidate the consequences of impaired DAergic modulation of astrocyte function on cerebellar-dependent
behaviors, which will have broad implications not only for RTT but also for other brain disorders associated
with cerebellar dysfunction.
项目总结/文摘
项目成果
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