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Glycine plays a dual role in the central nervous system as a fast inhibitory neurotransmitter and a co-agonist at N-methyl-D-aspartate receptors (NMDARs). Its extracellular levels are tightly regulated by two glycine transporters (GlyTs): GlyT1, which modulates glycine near excitatory synapses to influence glutamatergic transmission, and GlyT2, which sustains presynaptic glycine for inhibitory signalling. Dysregulation of GlyT function has been linked to numerous neurological and psychiatric disorders, including schizophrenia, mood and anxiety disorders, neurodegeneration, epilepsy, stroke, addiction, and pain. This review examines recent preclinical and clinical progress in targeting GlyTs, with an emphasis on GlyT1 inhibition to enhance NMDAR function. Among GlyT1 inhibitors, sarcosine shows consistent promise, particularly for schizophrenia and depressive symptoms. However, the limited clinical success of other compounds underscores challenges in translating preclinical efficacy. Addressing issues such as selectivity, patient stratification, and novel regulatory mechanisms will be key. Future research leveraging imaging biomarkers and next-generation pharmacological tools may help unlock the full therapeutic value of GlyTs.
Pinna et al. (Thu,) studied this question.