Understanding the temporal regulation of inhibitory synapse depression and elimination in the context of cerebral ischemia

了解脑缺血背景下抑制性突触抑制和消除的时间调节

基本信息

  • 批准号:
    10318089
  • 负责人:
  • 金额:
    $ 3.69万
  • 依托单位:
  • 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:
    2020-12-03 至 2022-12-02
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Inhibitory synapses are crucial for maintaining correct neuronal excitability, which is important for efficient circuitry and proper brain function. Shifts in neuronal excitability have been implicated in a variety of neurological disorders, including ischemia. Based on cell-type specific vulnerabilities, the oxygen and glucose deprivation (OGD) observed in various brain regions including the hippocampus leads to differential effects that may alter neuronal long-term function. The hippocampus is particularly a vulnerable brain region that experiences either delayed cell-death in the CA1 region or resistance to delayed-cell death and shifts in long-term excitability in the CA3 region. Cell-type specific synaptic alterations to neuronal populations may contribute to these ischemic-induced changes. Even though alterations at excitatory synapses are well defined, our knowledge of alterations at the inhibitory synapse remain elusive. Inhibitory GABAA receptors (GABAARs) mediate the majority of fast synaptic inhibition in the brain. The number of postsynaptic GABAARs influences inhibitory strength; therefore, GABAAR trafficking to and from synaptic sites or the neuronal surface is an important regulator of overall inhibitory synaptic strength. During OGD, GABAARs are downregulated from the neuronal surface in hippocampal neurons. Moreover, GABAAR phosphorylation status influences the synaptic declustering or removal of receptors from the neuronal surface during OGD in hippocampal neurons. However, mechanisms that regulate these differences in either synaptic clustering or surface GABAAR expression following an ischemic insult in brain regions with varying susceptibilities remain undefined. In this project, I propose that GABAAR declustering and endocytosis mechanisms are differentially regulated in distinct neuronal populations during OGD to influence GABAAR downregulation based on region-specific vulnerability. Moreover, I hypothesize that these cell-type specific mechanisms drive increased neuronal excitability during OGD due to increase synaptic declustering and decreased surface expression of GABAARs in vulnerable neuronal populations. Based on this, I plan to investigate (i) mechanisms of synaptic GABAAR declustering and surface downregulation in hippocampal pyramidal neurons following OGD (ii) probe the temporal regulation to determine the sequential flow of events promoting GABAAR loss and (iii) use an in vivo model of cerebral ischemia to compare cell-type specific mechanisms in CA1 and CA3 hippocampus that may be differentially regulated based on neuronal susceptibility to OGD. Specifically, I plan to investigate the role of phosphatases in regulating GABAAR phosphorylation state to promote GABAAR declustering and endocytosis during OGD in both vulnerable neuronal populations. The results of this project will establish mechanisms that are specific to GABAAR downregulation in vulnerable populations during OGD, providing novel targets for future therapeutic intervention.
项目总结/文摘

项目成果

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Joshua Daylon Garcia其他文献

Joshua Daylon Garcia的其他文献

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{{ truncateString('Joshua Daylon Garcia', 18)}}的其他基金

The role of dendritic excitatibility in controlling GABAergic synapse maturation
树突兴奋性在控制 GABA 能突触成熟中的作用
  • 批准号:
    10702002
  • 财政年份:
    2020
  • 资助金额:
    $ 3.69万
  • 项目类别:
Understanding the temporal regulation of inhibitory synapse depression and elimination in the context of cerebral ischemia
了解脑缺血背景下抑制性突触抑制和消除的时间调节
  • 批准号:
    10157074
  • 财政年份:
    2020
  • 资助金额:
    $ 3.69万
  • 项目类别:

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