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NR2 subunits and their role in striatal N-methyl-D-aspartate receptor function.

机译：NR2亚基及其在纹状体N-甲基-D-天冬氨酸受体功能中的作用。

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摘要

Converging glutamatergic and dopaminergic inputs from cortex, thalamus and substantia nigra are received by medium-sized spiny neurons (MSNs), the main cell population of the striatum. N-methyl-D-aspartate receptors (NMDARs) are a glutamate receptor subtype expressed by MSNs and these receptors consist of NR1, NR2A and/or NR2B subunits. Additionally, MSNs express dopamine receptors and subpopulations of MSNs primarily express either D1 (D1R) or D2 (D2R) dopamine receptors. The present study used genetic (transgenic mice) and pharmacological (NR2 antagonists) approaches to determine if NR2 subunits affect normal NMDA and dopamine receptor function in MSNs. In particular, questions regarding the topographic distribution of NR2A- and NR2B-expressing NMDARs were addressed along with the functional consequences of eliminating specific subtypes of NR2-expressing receptors. The most prominent contribution of NR2A-containing NMDARs was observed at synaptic sites while NR2B-containing receptors were found at both synaptic and extrasynaptic receptor locations. NMDAR-mediated current amplitudes were decreased and decay times were altered by deletion or blockade of NR2 subunits. The distribution of NR2-expressing NMDARs was also examined between D1R- and D2R-expressing MSNs. NR2 subunit distribution was different with NR2A contributing a larger component to NMDAR-mediated currents in D1R MSNs while NR2B did the opposite, contributing a larger component in D2R MSNs. Finally, NR2 subunits affect dopamine modulation of NMDAR-mediated currents. D1R potentiation was shown to be differentially affected by NR2 subunits with enhanced potentiation when the NR2A subunit was genetically deleted and there was a trend toward reduced potentiation when NR2B-expressing NMDARs were pharmacologically blocked. In contrast, D2R modulation was largely unaffected. Together, these data suggest that D2R-expressing MSNs of the indirect pathway are more vulnerable to excitotoxicity while dopamine modulation in direct pathway D1R-expressing MSNs is exclusively affected by shifts in NR2 subunit composition. Balance of the direct and indirect pathways is vital to normal basal ganglia function. Imbalances in these pathways occur in pathological conditions such as Huntington's and Parkinson's diseases and could involve alterations in NMDA and dopamine receptor interactions. Therefore, a better understanding of NR2 subunits and their contribution to these specific receptor interactions could lead to improved therapeutic approaches for these conditions.
机译：大脑皮层，丘脑和黑质汇合的谷氨酸能和多巴胺能输入被中型棘突神经元（MSN）接收，MSN是纹状体的主要细胞群。 N-甲基-D-天门冬氨酸受体（NMDARs）是MSNs表达的谷氨酸受体亚型，这些受体由NR1，NR2A和/或NR2B亚基组成。另外，MSN表达多巴胺受体，MSN的亚群主要表达D1（D1R）或D2（D2R）多巴胺受体。本研究使用遗传（转基因小鼠）和药理学（NR2拮抗剂）方法来确定NR2亚基是否影响MSN中的正常NMDA和多巴胺受体功能。特别是，解决了有关表达NR2A和NR2B的NMDAR的地形分布问题，以及消除了表达NR2的特定亚型的功能后果。在突触位点观察到了最显着的含NR2A NMDAR的贡献，而在突触和突触外受体的两个位置都发现了含NR2B的受体。 NMDAR介导的电流幅度降低，并且衰减时间因NR2亚基的缺失或阻断而改变。还检查了表达NR2的NMDAR在D1R和D2R的MSN之间的分布。 NR2亚基分布不同，其中NR2A对D1R MSN中的NMDAR介导的电流贡献更大的分量，而NR2B则相反，在D2R MSN中的贡献更大。最后，NR2亚基影响NMDAR介导的电流的多巴胺调节。当NR2A亚基被遗传删除时，D1R增强受NR2亚基增强影响的增强影响不同，当表达NR2B的NMDAR被药理学阻断时，D1R增强趋向于降低。相反，D2R调制在很大程度上不受影响。总之，这些数据表明，间接途径的表达D2R的MSN更易受到兴奋性毒性的影响，而直接途径表达D1R的MSNs中的多巴胺调节则仅受NR2亚基组成的变化影响。直接和间接途径的平衡对正常的基底神经节功能至关重要。这些途径的失衡发生在诸如亨廷顿氏病和帕金森氏病等病理状况中，并且可能涉及NMDA和多巴胺受体相互作用的改变。因此，对NR2亚基及其对这些特定受体相互作用的贡献的更好理解可以导致针对这些病症的改善的治疗方法。

著录项

  • 作者

    Jocoy, Emily Laura.;

  • 作者单位

    University of California, Los Angeles.;

  • 授予单位 University of California, Los Angeles.;
  • 学科 Biology Neuroscience.;Biology Neurobiology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 99 p.
  • 总页数 99
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:19

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