<br>抑郁症中连通性的改变：GABA 和谷氨酸神经递质的缺乏和新疗法的逆转,Neuron

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抑郁症中连通性的改变：GABA 和谷氨酸神经递质的缺乏和新疗法的逆转
Neuron ( IF 14.7 ) Pub Date : 2019-04-03 , DOI: 10.1016/j.neuron.2019.03.013
Ronald S Duman ₁ , Gerard Sanacora ₁ , John H Krystal ₁

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抑郁症和压力相关疾病的病理生理学和治疗机制尚不清楚，但对抑郁症患者和啮齿动物模型的研究已开始产生有希望的见解。这些研究表明，抑郁症和慢性压力暴露会导致与抑郁症有关的皮质和边缘脑区域的神经元萎缩，脑成像研究表明抑郁症患者大脑的连接性和网络功能发生了改变。对这些改变的神经生物学基础的研究集中在主要的兴奋性谷氨酸神经元和抑制性 GABA 中间神经元上。他们证明了两种主要神经元类型的结构、功能和神经化学缺陷，可能导致皮质和海马区域信号完整性退化。这些变化背后的分子机制尚未确定，但被认为与应激诱导的兴奋性毒性作用以及肾上腺糖皮质激素和炎症细胞因子以及其他环境因素升高有关。转录组学研究开始证明重要的性别差异，并与基因组研究一起开始揭示精神分裂症和双相情感障碍风险和病理生理机制的重叠和独特性机制领域。这些研究还涉及 GABA 和谷氨酸功能障碍以及免疫机制。虽然目前的抗抑郁药存在显着的时滞和疗效限制，但针对谷氨酸和 GABA 系统的新型速效药物可以解决这些问题，并为这种广泛存在的衰弱性疾病提供卓越的治疗干预措施。

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Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments

The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions. The molecular mechanisms underlying these changes have not been identified but are thought to be related to stress induced excitotoxic effects in combination with elevated adrenal glucocorticoids and inflammatory cytokines as well as other environmental factors. Transcriptomic studies are beginning to demonstrate important sex differences and, together with genomic studies, are starting to reveal mechanistic domains of overlap and uniqueness with regards to risk and pathophysiological mechanisms with schizophrenia and bipolar disorder. These studies also implicate GABA and glutamate dysfunction as well as immunologic mechanisms. While current antidepressants have significant time lag and efficacy limitations, new rapid-acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions for this widespread and debilitating disorder.

更新日期：2019-04-03

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