Metabotropic glutamate receptor-mediated synaptic plasticity in the basal ganglia

基底神经节代谢型谷氨酸受体介导的突触可塑性

基本信息

  • 批准号:
    8258278
  • 负责人:
  • 金额:
    $ 1.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-06-01 至 2013-05-31
  • 项目状态:
    已结题

项目摘要

The basal ganglia play a critical role in controlling voluntary movement and motor learning. Disruption of basal ganglia function causes devastating movement disorders such as Parkinson's disease (PD). In order to discover novel treatments for disorders such as PD, intense effort has been focused on understanding transmission in the basal ganglia in both normal and pathological states (DeLong and Wichmann, 2007). Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the basal ganglia and modulate synaptic transmission at every major synapse within the basal ganglia motor circuit (Conn et al., 2005). Understanding the function of mGluRs in the basal ganglia in normal and disease states has led to identification of several mGluR subtypes that may provide promising targets for pharmacological treatment of PD. We are particularly interested in the role of group II mGluRs (mGluR2 and mGluR3) at the synapse between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). The STN-SNr synapse is an excitatory synapse that plays a key role in regulating information output from the basal ganglia and is overactive in PD patients. Group II mGluRs regulate both acute and long- term depression (LTD) of excitatory transmission at the STN-SNr synapse (Bradley et al. 2000; Wittmann et al. 2002). For the proposed studies, I will use whole-cell electrophysiological techniques to measure excitatory postsynaptic currents from GABAergic SNr neurons in acute brain slices. First, I will use subtype-selective pharmacological tools that we have recently developed and mGluR2 and -3 knockout mice to determine which group II mGluR subtype(s) mediates acute and long-term effects of group II mGluR agonists on excitatory transmission. In addition, I will characterize the synaptic events involved in the induction of LTD in order to gain an increased understanding of the mechanisms underlying this novel form of synaptic plasticity. Finally, I will test the effect of dopamine depletion in order to understand how mGluR function might be altered in pathological states such as PD. Understanding how dopamine modulates mGluR function is important for the therapeutic potential of drugs targeting mGluRs for treating PD, as well as how changes in mGluR function may contribute to the pathogenesis of PD symptoms.
基底神经节在控制随意运动和运动学习中起着关键作用。基底神经节功能的破坏会导致破坏性的运动障碍,如帕金森病(PD)。为了发现PD等疾病的新治疗方法,人们一直致力于了解正常和病理状态下基底神经节中的传递(DeLong和Wichmann,2007)。代谢型谷氨酸受体(mGluR)是G蛋白偶联受体(GPCR),其在整个基底神经节中广泛表达并调节基底神经节运动回路内每个主要突触处的突触传递(Conn et al.,2005年)。了解正常和疾病状态下基底神经节中mGluR的功能,已经鉴定出几种mGluR亚型,这些亚型可能为PD的药物治疗提供有希望的靶点。我们特别感兴趣的作用,第二组mGluRs(mGluR 2和mGluR 3)之间的突触丘脑底核(ESTA)和黑质网状部(SNr)。STN-SNr突触是一种兴奋性突触,在调节基底神经节的信息输出中起关键作用,并且在PD患者中过度活跃。II组mGluR调节STN-SNr突触处兴奋性传递的急性和长期抑制(LTD)(布拉德利等人,2000; Wittmann等人,2002)。对于所提出的研究,我将使用全细胞电生理技术来测量兴奋性突触后电流从GABA能SNr神经元在急性脑切片。首先,我将使用我们最近开发的亚型选择性药理学工具和mGluR 2和mGluR 3基因敲除小鼠来确定哪种II组mGluR亚型介导II组mGluR激动剂对兴奋性传递的急性和长期影响。此外,我将描述参与LTD诱导的突触事件,以增加对这种新型突触可塑性机制的理解。最后,我将测试多巴胺耗竭的影响,以了解mGluR功能如何在PD等病理状态下改变。了解多巴胺如何调节mGluR功能对于靶向mGluR治疗PD的药物的治疗潜力以及mGluR功能的变化如何有助于PD症状的发病机制是重要的。

项目成果

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Kari Johnson其他文献

Kari Johnson的其他文献

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{{ truncateString('Kari Johnson', 18)}}的其他基金

Thalamostriatal circuit contributions to behavioral inflexibility following adolescent ethanol exposure
青少年乙醇暴露后丘脑纹状体回路对行为僵化的影响
  • 批准号:
    10354795
  • 财政年份:
    2022
  • 资助金额:
    $ 1.17万
  • 项目类别:
Thalamostriatal circuit contributions to behavioral inflexibility following adolescent ethanol exposure
青少年乙醇暴露后丘脑纹状体回路对行为僵化的影响
  • 批准号:
    10579844
  • 财政年份:
    2022
  • 资助金额:
    $ 1.17万
  • 项目类别:
Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure
慢性乙醇暴露后皮质纹状体传递的突触前调节
  • 批准号:
    10020296
  • 财政年份:
    2017
  • 资助金额:
    $ 1.17万
  • 项目类别:
Presynaptic modulation of corticostriatal transmission following chronic ethanol exposure
慢性乙醇暴露后皮质纹状体传递的突触前调节
  • 批准号:
    10241461
  • 财政年份:
    2017
  • 资助金额:
    $ 1.17万
  • 项目类别:
Metabotropic glutamate receptor-mediated synaptic plasticity in the basal ganglia
基底神经节代谢型谷氨酸受体介导的突触可塑性
  • 批准号:
    8097569
  • 财政年份:
    2010
  • 资助金额:
    $ 1.17万
  • 项目类别:
Metabotropic glutamate receptor-mediated synaptic plasticity in the basal ganglia
基底神经节代谢型谷氨酸受体介导的突触可塑性
  • 批准号:
    7909971
  • 财政年份:
    2010
  • 资助金额:
    $ 1.17万
  • 项目类别:

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