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Astrocyte regulation of synapse maturation

星形胶质细胞对突触成熟的调节

基本信息

批准号：
9501523
负责人：
Nicola J Allen
金额：
$ 42.09万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9501523
关键词：
Address Adult Astrocytes Autistic Disorder Biochemical Biological Assay Brain Calcium Cell Culture System Cells Communication Data Development Disease Event Excision Excitatory Synapse Eye Fractionation Genetic Transcription Glutamate Receptor Glypican Growth Human Impairment In Vitro Kinetics Knockout Mice LIMK1 gene Learning Long-Term Depression Long-Term Potentiation Mass Spectrum Analysis Mediating Molecular Mus Mutation Neuraxis Neurons Neurotransmitters Pathway interactions Pattern Performance Permeability Process Property Proteins Regulation Role Schizophrenia Sensory Signal Transduction Slice Surface Synapses Synaptic Transmission Synaptic plasticity Testing Thalamic structure Time Vertebral column Visual Cortex Visual system structure Work base cell type chordin cognitive testing critical period experience experimental study in vivo insight monocular deprivation morphogens nerve supply nervous system disorder neuronal patterning novel postnatal postsynaptic recruit repaired response sensory input

项目摘要

In the developing brain excitatory synapses first form containing calcium permeable AMPA glutamate receptors (AMPARs), which are replaced by GluA2 containing calcium impermeable AMPARs as synapses stabilize and mature. The switch from calcium-permeable to calcium-impermeable AMPARs contributes to synapse maturation and limits subsequent synaptic plasticity, by limiting the entry of calcium into the postsynaptic cell. Studies have shown that the presence of astrocytes is sufficient to increase surface and synaptic levels of all 4 AMPAR subunits (GluA1-4) in neurons, and have identified glypicans 4 & 6 as astrocyte-secreted signals that specifically recruit GluA1 calcium-permeable AMPARs to synapses, with no effect on GluA2. This raised the hypothesis that astrocytes can regulate the subunit composition of AMPARs at synapses by releasing distinct signals, which has the potential to alter synapse maturation and plasticity. A screen was conducted to identify the GluA2 recruiting factor and identified the astrocyte-secreted BMP antagonist chordin like 1 (Chrdl1). Addition of Chrdl1 to neurons in vitro is sufficient to increase synaptic clustering of GluA2, and to induce functionally mature synapses to form. In vivo, Chrdl1 is specifically expressed by astrocytes in the mouse brain and absent from neurons. Expression of Chrdl1 is restricted to cortical astrocytes, and within the cortex expression is higher in astrocytes in upper cortical layers compared to deep, and peaks at the time of synapse maturation and synaptic recruitment of GluA2. Mice globally lacking Chrdl1 show evidence of delayed synapse maturation, with altered kinetics of synaptic transmission and decreased levels of GluA2 at excitatory synapses. This proposal investigates unanswered questions related to: 1) how Chrdl1 is interacting with neurons to recruit GluA2 to synapses, 2) what regulates the regional and temporal expression of Chrdl1 in astrocytes, 3) whether lack of Chrdl1 in vivo enhances synaptic plasticity. Aim 1 investigates whether Chrdl1 is acting in its known role as a secreted antagonist of BMP signaling, either through the canonical BMP pathway or in a non-canonical mechanism. Aim 2 asks if the in vivo expression pattern of Chrdl1 is due to specific patterns of neuronal innervation, and asks what is the signal from neurons that induces Chrdl1 in astrocytes. In Aim 3, the question of whether the impaired synapse maturation and immature synapses observed in Chrdl1 KO mice leads to enhanced synaptic plasticity is investigated in the visual system, by looking at the role of Chrdl1 in critical period plasticity. These experiments will give important mechanistic insight into how synapse maturation is controlled in the developing brain, and the role of astrocytes in this process.

在发育中的大脑兴奋性突触的第一种形式含有钙渗透性AMPA谷氨酸受体