Ohgi Y, Futamura T, Hashimoto K
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1- 8-1 Inohana, Chiba 260-8670, Japan.
Curr Mol Med. 2015;15(3):206-21. doi: 10.2174/1566524015666150330143008.
Glutamate, a major excitatory neurotransmitter, plays important roles in synaptic plasticity, such as long-term potentiation (LTP) and new synapse formation. Growing evidence suggests that glutamate signaling is involved in the neurobiology of psychiatric disorders, including schizophrenia, major depressive disorder (MDD) and bipolar disorder (BP). Postmortem brain studies demonstrated altered spine density in brains from patients with these psychiatric disorders, indicating that remodeled neuronal circuits may contribute to the pathobiology of these psychiatric diseases. Drugs targeting the glutamate system have typically attracted attention as they show efficacy in animal studies and potential therapeutic effects in the clinical setting. In particular, the Nmethyl- D-aspartate (NMDA) receptor antagonist, ketamine exerts a rapid and robust antidepressant effect in treatment-resistant patients with MDD and BP, whereas conventional antidepressants require several weeks for therapeutic onset. Animal studies showed that ketamine induced rapid synaptogenesis, suggestive of synaptic plasticity via NMDA receptor signaling being an essential event in the treatment of depression. Therefore, drugs modulating glutamate signaling could also be potential therapeutic drugs for psychiatric disorders. First, we summarize the role of glutamate signaling on dendritic spine formation, maintenance and remodeling. Then, we discuss the abnormalities identified in dendritic spine and glutamate signaling from postmortem brain studies and animal models of psychiatric disorders. Finally, we review the potential benefits of drugs acting on the NMDA receptor in clinical and animal models of psychiatric disorders.
谷氨酸是一种主要的兴奋性神经递质，在突触可塑性中发挥重要作用，如长时程增强（LTP）和新突触形成。越来越多的证据表明，谷氨酸信号传导参与了包括精神分裂症、重度抑郁症（MDD）和双相情感障碍（BP）在内的精神疾病的神经生物学过程。尸检脑研究表明，这些精神疾病患者大脑中的脊柱密度发生了改变，这表明重塑的神经回路可能促成了这些精神疾病的病理生物学过程。靶向谷氨酸系统的药物通常备受关注，因为它们在动物研究中显示出疗效，并在临床环境中具有潜在的治疗效果。特别是，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮对难治性MDD和BP患者具有快速而强大的抗抑郁作用，而传统抗抑郁药需要数周时间才能起效。动物研究表明，氯胺酮可诱导快速的突触形成，提示通过NMDA受体信号传导的突触可塑性是抑郁症治疗中的一个关键事件。因此，调节谷氨酸信号传导的药物也可能是治疗精神疾病的潜在药物。首先，我们总结了谷氨酸信号传导在树突棘形成、维持和重塑中的作用。然后，我们讨论了在精神疾病的尸检脑研究和动物模型中发现的树突棘和谷氨酸信号传导异常。最后，我们回顾了作用于NMDA受体的药物在精神疾病临床和动物模型中的潜在益处。
