TRANSPORTER REGULATION OF GABAB-MEDIATED TRANSMISSION IN THE THALAMUS

丘脑中 GABAB 介导的传输的转运蛋白调节

• 批准号: 8364180
• 负责人: John R Huguenard
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364180
• 关键词: 3-Dimensional; Accounting; Affect; Algorithms; Biomedical Research; Complex; Data; Diffuse; Diffusion; Distal; Electrophysiology (science); Environment; Funding; GABA transporter; Grant; High Performance Computing; Kinetics; Mediating; Modeling; National Center for Research Resources; Nature; Principal Investigator; Property; Rattus; Receptor Activation; Regulation; Research; Research Infrastructure; Resources; Role; Running; Site; Source; Suggestion; Supercomputing; Synapses; Thalamic structure; United States National Institutes of Health; cost; density; extracellular; gamma-Aminobutyric Acid; neurotransmitter release; neurotransmitter uptake; postsynaptic; receptor; response; synaptic inhibition; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Many factors ranging from neurotransmitter release to receptor localization to neurotransmitter uptake mechanisms will affect GABA-mediated synaptic inhibition, especially for metabotropic (GABAB-mediated) responses. As postsynaptic GABAB receptors are localized primarily outside of synaptic sites (ie extrasynaptic), it is hypothesized that GABA transporters (GATs), which function to remove extracellular GABA, limit the extent of GABA spillover and, therefore, GABAB receptor activation. To better understand how GATs regulate GABA spillover, we are examining the roles of two GATs, GAT1 and GAT3, in defining features of GABAB IPSCs in the rat thalamus. Our electrophysiology data demonstrate that GAT1 and GAT3 differentially regulate the amplitude and kinetics of GABAB IPSCs. Our anatomical data suggest that these different GAT1/3 actions result from differences in subcellular localization and density of the two GATs. Specifically, GAT1 expression is primarily perisynaptic, while GAT3 is found in both peri- and more distal extra-synaptic regions. We are beginning to explore how such differential localization can influence GABAB currents. We are currently using computational approaches to explore how GAT localization regulates GABA diffusion in the thalamus, and how such regulation determines the properties of GABAB IPSCs. Specifically, we are using MCell, a modeling platform that tracks the stochastic nature of diffusing molecules in 3-dimensional microphysiological environments using Monte Carlo algorithms (Stiles and Bartol, 2001). Our simpler, less computationally-intensive models indicate that differential GAT1/3 localization provides a mechanism by which GABA transients can be modulated to enable distinct GABAB IPSC amplitude and kinetic changes. We now would like to verify these initial findings in more complex models. Dr. Joel Stiles suggested that we utilize resources offered by the Pittsburg Supercomputing Center to run our new models. Therefore, in following his suggestion, we are applying for these resources to complete our project. We would like user accounts for Mark Beenhakker and John Huguenard

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 从神经递质释放到受体定位到神经递质摄取机制的许多因素都会影响GABA介导的突触抑制作用，特别是对于代孕剂（GABAB介导的）反应。由于突触后GABAB受体主要在突触部位（IE外突触）之外进行局部局部，因此假设GABA转运蛋白（GAT）功能可去除细胞外GABA，限制GABA溢出的程度，从而限制GABAB受体激活的程度。为了更好地理解GAT如何调节GABA溢出，我们正在研究两个GATS GAT1和GAT3在定义大鼠Thalamus中GABAB IPSC的特征中的作用。我们的电生理数据表明，GAT1和GAT3差异地调节了GABAB IPSC的振幅和动力学。我们的解剖学数据表明，这些不同的GAT1/3动作是由于两个GAT的亚细胞定位和密度差异而产生的。具体而言，GAT1的表达主要是直发性，而GAT3在周围和远端突触外区域都发现。我们开始探索这种差异定位如何影响GABAB电流。我们目前正在使用计算方法来探索GAT定位如何调节丘脑中的GABA扩散，以及该调节如何确定GABAB IPSC的性质。具体而言，我们使用的是Mcell，它是一种建模平台，该平台跟踪使用蒙特卡洛算法在三维微生物生理环境中扩散分子的随机性质（Stiles和Bartol，2001）。我们更简单，更少的计算密集型模型表明，差异GAT1/3定位提供了一种机制，可以调节GABA瞬变以实现不同的GABAB IPSC振幅和动力学变化。现在，我们想在更复杂的模型中验证这些初始发现。乔尔·斯蒂尔斯（Joel Stiles）博士建议，我们利用匹兹堡超级计算中心提供的资源来运行我们的新型号。因此，在遵循他的建议时，我们正在申请这些资源来完成我们的项目。我们希望Mark Beanhakker和John Huguenard的用户帐户