TAAR1 Modulates Cortical Glutamate NMDA Receptor Function
TAAR1 Modulates Cortical Glutamate NMDA Receptor Function
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DOI：
10.1038/npp.2015.65
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发表时间：
2015-08-01
影响因子：
7.6
通讯作者：
Gainetdinov, Raul R.
中科院分区：
文献类型：
--
作者：
Espinoza, Stefano;Lignani, Gabriele;Gainetdinov, Raul R.
痕量胺相关受体1（TAAR 1）是在哺乳动物脑中表达的G蛋白偶联受体，并且已知影响皮质下单胺能传递。单胺，如多巴胺，也在前额叶皮层（PFC）回路中发挥重要作用，这与高级认知过程密切相关。TAAR 1选择性配体在实验动物模型中显示出潜在的抗精神病、抗抑郁和促认知作用;然而，TAAR 1是否能影响PFC相关的过程和功能仍不清楚。在这项研究中，我们记录了一个独特的模式TAAR 1在PFC中的表达，以及改变亚基组成和功能缺陷的谷氨酸N-甲基-D-天冬氨酸（NMDA）受体在PFC的第五层的锥体神经元在小鼠缺乏TAAR 1。TAAR 1-KO小鼠中皮质谷氨酸传递失调与几项测试中的异常行为相关，表明突变体的持续和冲动表型。相反，在正常小鼠中，用选择性激动剂药理学激活TAAR 1减少了在固定间隔条件反射时间表中观察到的过早冲动反应。我们的研究表明，TAAR 1在调节PFC中NMDA受体介导的谷氨酸传递及相关功能中起重要作用。此外，这些数据表明，开发基于TAAR 1的药物可以为治疗与异常皮质功能相关的疾病提供一种新的治疗方法。
Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions.