de Bartolomeis Andrea, Manchia Mirko, Marmo Federica, Vellucci Licia, Iasevoli Felice, Barone Annarita
Laboratory of Molecular Psychiatry and Translational Psychiatry, Unit of Treatment Resistant Psychosis, Section of Psychiatry, Department of Neuroscience, Reproductive Science and Odontostomatology, University School of Medicine of Napoli Federico II, Naples, Italy.
Section of Psychiatry, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy.
Front Psychiatry. 2020 May 14;11:369. doi: 10.3389/fpsyt.2020.00369. eCollection 2020.
Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine - glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.
难治性精神分裂症（TRS）或对抗精神病药物反应欠佳影响了近30%的精神分裂症（SCZ）患者，这是一个相关的临床问题，对功能结局和全球疾病负担有重大影响。在假定的新型治疗方法中，基于强有力的临床前理论依据，已提出以甘氨酸为中心的治疗药物（即肌氨酸、甘氨酸本身、D-丝氨酸和比特肽），然而临床结果喜忧参半。因此，有必要更好地评估甘氨酸与SCZ病理生理学中其他主要因素的相互作用，特别是在多巴胺-谷氨酸相互作用的框架内。前沿技术和药物发现的新方法已被应用于研究甘氨酸在谷氨酸信号传导中的作用，包括突触前和突触后水平，并且有助于揭示甘氨酸在多巴胺-谷氨酸相互作用中的作用。甘氨酸是一种非必需氨基酸，在抑制性和兴奋性神经传递中都起着关键作用。在中枢神经系统（CNS）的尾部区域，如脊髓和脑干，甘氨酸通过与其受体即甘氨酸受体（GlyR）结合，作为一种强大的抑制性神经递质发挥作用。然而，甘氨酸在兴奋性谷氨酸能神经传递中也作为N-甲基-D-天冬氨酸受体（NMDAR）的协同激动剂起作用。突触间隙中的甘氨酸浓度由甘氨酸转运体即GlyT1和GlyT2精细调节，它们调节神经递质的再摄取，其中第一个被认为是精神病治疗的一个极具潜力的靶点。本文探讨了前脑中多巴胺和甘氨酸的相互调节、甘氨酸对谷氨酸的调节、甘氨酸信号与谷氨酸能突触处突触后致密蛋白的相互作用以及SCZ中甘氨酸能途径的人类遗传学，以突出这种神经递质和相关分子在SCZ和TRS中的应用。
