Uncoupling the D1-N-Methyl-D-Aspartate (NMDA) Receptor Complex Promotes NMDA-Dependent Long-Term Potentiation and Working Memory
Uncoupling the D1-N-Methyl-D-Aspartate (NMDA) Receptor Complex Promotes NMDA-Dependent Long-Term Potentiation and Working Memory
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DOI：
10.1016/j.biopsych.2009.08.011
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发表时间：
2010-02-01
影响因子：
10.6
通讯作者：
Liu, Fang
中科院分区：
文献类型：
--
作者：
Nai, Qiang;Li, Shupeng;Liu, Fang
背景：虽然多巴胺D_1受体参与了工作记忆，但D_1受体如何参与这一过程尚不清楚。大量研究表明，D1受体与N-甲基-D-天冬氨酸(NMDA)受体具有广泛的功能相互作用。本课题组先前证实，D1R通过与NMDA受体NR1a和NR2a亚基的羧基末端直接的蛋白质-蛋白质相互作用来调节NMDA受体的功能。在本研究中，我们利用TAT结合的干扰肽(TAT-D_1-T_2)，探讨了D1NR1相互作用对NMDA受体依赖的长时程增强(LTP)和工作记忆的影响。在特定的实验条件下，分别检测海马片和海马神经元中的免疫共沉淀和钙/钙调素依赖的蛋白激酶II(CaMKII)活性。结果：电生理实验显示，D1R的激活以CaMKII依赖的方式上调NMDA受体介导的LTIP。此外，D1R激动剂刺激促进NR1-CaMKII偶联，增强CaMKII活性，D1R介导的作用可被TAT-D1T2多肽阻断。有趣的是，注射TAT-D1-T2多肽的动物表现出显著的工作记忆损害。结论：我们的研究表明，NMDA-D1直接的蛋白质-蛋白质相互作用在NMDA受体介导的LTP和工作记忆中起着关键作用，并暗示CaMKII参与了这一过程。
Background: Although dopamine D1 receptors are involved in working memory, how D1 receptors contribute to this process remains unclear. Numerous studies have shown that D1 receptors have extensive functional interaction with N-methyl-D-aspartate (NMDA) receptor. Our group previously demonstrated that D1 receptors were able to regulate NMDA receptor functions through direct protein-protein interactions involving the carboxyl terminals of D1 receptors and NMDA receptor NR1a and NR2A subunits respectively. In this study, we explored the effects of the D1-NR1 interaction on NMDA receptor-dependent long-term potentiation (LTP) and working memory by using the TAT-conjugated interfering peptide (TAT-D1-t2).Methods: Miniature excitatory postsynaptic currents are recorded in rat hippocampal primary cultures. Coimmunoprecipitation and calcium/calmodulin-dependent protein kinase II (CaMKII) activity are measured in hippocampal slices and hippocampal neurons under the specified experimental conditions, respectively. Working memory was assessed using a delayed match-to-place protocol in the MorrisWaterMaze following administration of the TAT-D1-t2 peptide.Results: Electrophysiology experiments showed that activation of D1 receptor upregulates NMDA receptor-mediated LTIP in a CaMKII-dependent manner. Furthermore, D1 receptor agonist stimulation promotes the NR1-CaMKII coupling and enhances the CaMKII activity; and the D1 receptor-mediated effects can be blocked by the application of the TAT-D1-t2 pepticle. Interestingly, animals injected with TAT-D1-t2 pepticle exhibited significantly impaired working memory.Conclusions: Our study showed a critical role of NMDA-D1 direct protein-protein interaction in NMDA receptor-mediated LTP and working memory and implicated the involvement of CaMKII in this process.