AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression
AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression
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DOI：
10.1096/fj.08-106450
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发表时间：
2008-09-01
期刊：
影响因子：
4.8
通讯作者：
Gass, P.
中科院分区：
文献类型：
--
作者：
Chourbaji, S.;Vogt, M. A.;Gass, P.
最近的证据表明，谷氨酸稳态和神经传递在重度抑郁症中发生了改变，但这种破坏的性质及其导致该综合征的机制尚不清楚。谷氨酸可以通过 AMPA、NMDA 或代谢型受体发挥作用。通过靶向诱变，我们在此证明，缺失主要 AMPA 受体亚基 GluR-A 的小鼠代表了具有良好面部和结构有效性的抑郁症模型，显示了人类患者也假设的抑郁症的行为和神经化学特征。 GluR-A(-/-) 小鼠表现出习得性无助增加、血清素和去甲肾上腺素水平降低、谷氨酸稳态紊乱、谷氨酸水平增加和 NMDA 受体表达增加。这些结果与当前关于 AMPA 和 NMDA 受体在抑郁症中的作用的概念非常吻合，假设增强 AMPA 受体信号传导或降低 NMDA 受体功能的化合物具有抗抑郁作用。 GluR-A(-/-) 小鼠代表了一个模型，用于研究抑郁表型背后的病理生理学，并识别由谷氨酸能功能的遗传改变引起的神经可塑性和弹性的变化。此外，GluR-A(-/-) 小鼠可能是研究 AMPA 受体调节剂的生物学机制以及 NMDA 拮抗剂在减少与无助感增加相关的行为或生化变化方面的功效的有价值的工具。
Recent evidence indicates that glutamate homeostasis and neurotransmission are altered in major depressive disorder, but the nature of the disruption and the mechanisms by which it contributes to the syndrome are unclear. Glutamate can act via AMPA, NMDA, or metabotropic receptors. Using targeted mutagenesis, we demonstrate here that mice with deletion of the main AMPA receptor subunit GluR-A represent a depression model with good face and construct validity, showing behavioral and neurochemical features of depression also postulated for human patients. GluR-A(-/-) mice display increased learned helplessness, decreased serotonin and norepinephrine levels, and disturbed glutamate homeostasis with increased glutamate levels and increased NMDA receptor expression. These results correspond well with current concepts regarding the role of AMPA and NMDA receptors in depression, postulating that compounds that augment AMPA receptor signaling or decrease NMDA receptor functions have antidepressant effects. GluR-A(-/-) mice represent a model to investigate the pathophysiology underlying the depressive phenotype and to identify changes in neural plasticity and resilience evoked by the genetic alterations in glutamatergic function. Furthermore, GluR-A(-/-) mice may be a valuable tool to study biological mechanisms of AMPA receptor modulators and the efficacy of NMDA antagonists in reducing behavioral or biochemical changes that correlate with increased helplessness.