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Impaired Astroglial Glutamate Signaling in Rett Syndrome

Rett 综合征中星形胶质细胞谷氨酸信号传导受损

基本信息

批准号：
10116102
负责人：
Wei Li
金额：
$ 40.84万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116102
关键词：
Adrenergic alpha-Antagonists Affect Astrocytes Behavior Behavior assessment Behavioral Brain Brain Diseases Cells Confocal Microscopy Corpus striatum structure Data Dopamine Equilibrium Etiology Excitatory Synapse Female Functional disorder Gait Genes Genetic Transcription Glutamate Transporter Glutamates Grooming Hand functions Homeostasis Human Image Impairment Individual Knockout Mice Learning Link Locomotion Long-Term Depression Long-Term Potentiation Machine Learning Mediating Membrane Methyl-CpG-Binding Protein 2 Mosaicism Motor Motor Activity Mus Mutation Neuroglia Neurons Pathologic Pharmacology Play Presynaptic Terminals Resolution Rett Syndrome Role Seizures Signal Transduction Slice Speech Synapses Synaptic Transmission Synaptic plasticity Testing Time Walking Whole-Cell Recordings Woman Work autism spectrum disorder base cell type conditional knockout extracellular field study glutamatergic signaling imaging system in vivo learning classifier loss of function mutation motor control motor deficit mouse model neuronal circuitry optogenetics overexpression repetitive behavior sensory integration severe intellectual disability

项目摘要

ABSTRACT Rett syndrome (RTT) is a leading cause of severe intellectual disability in women. Individuals with RTT develop typically until 6-18 months, when autism-like behaviors as well as deficits in purposeful hand use and speech start to develop. Loss-of-function mutations in the X-linked transcriptional regulator methyl-CpG-binding protein 2 (MECP2) occur in >95% of RTT cases. Initially, MeCP2 deficiency in neurons was considered as the exclusive cause of RTT, but recent studies have revealed that glial cells lacking functional MeCP2 also have a significant pathological role in RTT etiology. However, specific cellular mechanisms of glial cell dysfunction underlying this role or its behavioral consequences have not been identified. In this study, we propose to examine the contribution of a specific glial subtype, astrocytes, to the dysfunction of the striatum responsible for motor deficits in a Mecp2-based mouse model for RTT. Astrocytes expressing the Slc1a2 gene encoding glutamate transporter-1 (GLT-1, also EAAT2) have a pivotal role in regulating extracellular glutamate levels. We propose to characterize the contribution of GLT-1 dysfunction to glutamate signaling in conditional knockout (cKO) mice lacking Mecp2 only in astrocytes using a combination of experimental approaches, including whole-cell intracellular recordings and optogenetics in striatal slices, time-lapse imaging of intracellular Ca2+ and extracellular glutamate and dopamine, near-super resolution confocal microscopy, and quantitative behavioral assessments using machine-learning classifiers. Our preliminary results indicate lower expression levels of Slc1a2 in the striatum of constitutive Mecp2 KO mice, consistent with smaller GLT-1-mediated intracellular Na+ signals and membrane currents in striatal astrocytes. Intriguingly, Mecp2 cKO mice show higher locomotor activity in the open field test. We also present preliminary evidence of the role of GLT-1 in modulating extracellular glutamate levels, intracellular Ca2+ dynamics in astrocytes, and dopamine release from dopaminergic terminals. Based on prior work and these preliminary results, we hypothesize that astroglial glutamate signaling in the striatum is impaired in Mecp2 deficient mice and contributes to their motor deficits. We propose two Specific Aims: (1) Identify and characterize the cellular consequences of GLT-1 dysfunction in cKO mice lacking Mecp2 in astrocytes, and (2) Characterize neuronal network activity and striatum-related behaviors in cKO mice lacking Mecp2 in astrocytes. The proposed studies will elucidate the consequences of MeCP2 loss in astrocyte GLT-1 function on striatum-dependent behaviors, which will have broad implications not only for RTT but also for other brain disorders associated with striatal dysfunction.

文摘