An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia
An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia
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DOI：
10.1038/npp.2016.2
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发表时间：
2016-07-01
影响因子：
7.6
通讯作者：
Coyle, Joseph T.
中科院分区：
文献类型：
--
作者：
Balu, Darrick T.;Li, Yan;Coyle, Joseph T.
有大量证据表明，NMDA受体（NMDAR）功能低下有助于精神分裂症（SCZ）的病理生理。最近的一项大规模全基因组关联研究确定丝氨酸消旋酶（SR），产生NMDAR共激动剂D-丝氨酸的酶，作为SCZ的风险基因。丝氨酸消旋酶敲除（SR-/-）小鼠，缺乏D-丝氨酸，表现出许多在SCZ中观察到的神经化学和行为异常。代谢型谷氨酸受体5（mGlu（5））阳性变构调节剂（PAM）目前正在开发用于治疗认知功能障碍。我们使用体外电生理学来确定mGlu（5）PAM VU0409551是否直接增强成年雄性SR-/-小鼠海马切片中的NMDAR功能。我们向成年雄性野生型C57 BL/6动物全身施用VU 0409551 5天，以确定在SR-/-小鼠中测试的最佳剂量。我们使用蛋白质印迹分析和微量恐惧条件反射来确定VU 0409551处理5天是否可以分别逆转SR-/-小鼠的神经可塑性和学习缺陷。我们表明，VU0409551增强NMDAR功能，并挽救从SR-/-小鼠获得的海马切片的长时程增强。用VU040955 1（10和30 mg/kg）对野生型小鼠进行全身治疗导致Akt/GS3K α/β信号传导途径的剂量依赖性增加，其在SR-/-小鼠和SCZ中减少。此外，向SR-/-小鼠施用VU 0409551逆转了它们在几种神经可塑性信号传导途径中的缺陷，并改善了它们的情境恐惧记忆。这些结果支持mGlu（5）的正变构调节，特别是用VU 0409551，作为逆转已知在SCZ中受损的NMDAR功能、突触可塑性和记忆的缺陷的可行机制。
There is substantial evidence that NMDA receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia (SCZ). A recent large-scale genome-wide association study identified serine racemase (SR), the enzyme that produces the NMDAR co-agonist D-serine, as a risk gene for SCZ. Serine racemase knockout (SR-/-) mice, which lack D-serine, exhibit many of the neurochemical and behavioral abnormalities observed in SCZ. Metabotropic glutamate receptor 5 (mGlu(5))-positive allosteric modulators (PAMs) are currently being developed to treat cognitive dysfunction. We used in vitro electrophysiology to determine whether the mGlu(5) PAM VU0409551 directly enhances NMDAR function in hippocampal slices from adult male SR-/- mice. We administered VU0409551 systemically for 5 days to adult male wild-type C57BL/6 animals to determine the optimal dose to test in SR-/- mice. We used western blot analyses and trace-fear conditioning to determine whether 5 days of VU0409551 treatment could reverse the neuroplasticity and learning deficits, respectively, in SR-/- mice. We show that VU0409551 enhances NMDAR function and rescues long-term potentiation in hippocampal slices obtained from SR-/- mice. Systemic treatment with VU040955 1 (10 and 30 mg/kg) to wild-type mice causes a dose-dependent increase in the Akt/GS3K alpha/beta signaling pathway, which is reduced in SR-/- mice and in SCZ. Furthermore, the administration of VU0409551 to SR-/- mice reverses their deficits in several neuroplasticity signaling pathways and improves their contextual fear memory. These results support positive allostedc modulation of mGlu(5), particularly with VU0409551, as a viable mechanism to reverse the deficits in NMDAR function, synaptic plasticity, and memory that are known to be impaired in SCZ.