谷氨酸是大脑中主要的兴奋性神经递质,其中它控制认知功能域和情绪。的确,涉及记忆形成和巩固以及恐惧和情绪处理的大脑区域,比如海马,前额叶皮质,和杏仁核,主要是谷氨酸能的。为了确保大脑的生理活动,谷氨酸能传递在突触部位进行微调。破坏负责谷氨酸稳态的机制可能导致过量谷氨酸水平的积累,这反过来又导致钙水平增加,线粒体异常,氧化应激,最终细胞萎缩和死亡。这种情况被称为谷氨酸诱导的兴奋性毒性,被认为是几种中枢神经系统疾病的致病机制,包括神经发育,药物滥用,和精神疾病。另一方面,这些疾病在谷氨酸能大脑区域共享神经可塑性损伤,伴随着谷氨酸能神经元的结构重塑。在当前的叙述审查中,我们将总结谷氨酸诱导的兴奋性毒性在神经发育和成人精神疾病的病理生理学和治疗干预中的作用,重点是自闭症谱系障碍,药物滥用,和精神疾病。的确,谷氨酸能药物正在临床前和临床开发中,用于治疗共有谷氨酸能神经可塑性障碍的不同精神疾病。尽管临床证据仍然有限,需要更多的研究,谷氨酸稳态的调节作为控制脑疾病的一个潜在的关键目标正引起人们的注意。
Glutamate is the main excitatory neurotransmitter in the brain wherein it controls cognitive functional domains and mood. Indeed, brain areas involved in memory formation and consolidation as well as in fear and emotional processing, such as the hippocampus, prefrontal cortex, and amygdala, are predominantly glutamatergic. To ensure the physiological activity of the brain, glutamatergic transmission is finely tuned at synaptic sites. Disruption of the mechanisms responsible for glutamate homeostasis may result in the accumulation of excessive glutamate levels, which in turn leads to increased calcium levels, mitochondrial abnormalities, oxidative stress, and eventually cell atrophy and death. This condition is known as glutamate-induced excitotoxicity and is considered as a pathogenic mechanism in several diseases of the central nervous system, including
neurodevelopmental, substance abuse, and psychiatric disorders. On the other hand, these disorders share neuroplasticity impairments in glutamatergic brain areas, which are accompanied by structural remodeling of glutamatergic neurons. In the current narrative review, we will summarize the role of glutamate-induced excitotoxicity in both the pathophysiology and therapeutic interventions of
neurodevelopmental and adult mental diseases with a focus on autism spectrum disorders, substance abuse, and psychiatric disorders. Indeed, glutamatergic drugs are under preclinical and clinical development for the treatment of different mental diseases that share glutamatergic neuroplasticity dysfunctions. Although clinical evidence is still limited and more studies are required, the regulation of glutamate homeostasis is attracting attention as a potential crucial target for the control of brain diseases.