The high-affinity glycine transporter 1 (GlyT1) is the primary endogenous regulator of glycine levels in the vicinity of the N-methyl-D-aspartate receptor (NMDAR). As a co-agonist, glycine can allosterically modulate NMDAR functions through its binding to the glycine binding site (glycine-B site). Under homeostatic conditions, GlyT1 mediated re-uptake is believed to maintain the synaptic glycine concentration below the saturation level of the glycine-B site. Given that glycine-B site occupation is obligatory for glutamatergic activation of the NMDAR, increased availability of glycine in the vicinity of NMDARs glycine-B site has been suggested as an alternate strategy to enhance NMDAR functions. Because exogenously administered glycine shows poor blood-brain barrier penetration and must overcome potent regulatory brain mechanisms in order to efficiently enhance NMDAR function, one currently favored strategy is to target the glycine clearance mechanism through inhibition of GlyT1 mediated re-uptake. Numerous studies have demonstrated that pharmacological blockade or molecular down-regulation of GlyT1 leads to enhanced NMDAR functions and thus may provide novel therapeutic avenues in the treatment of neurological and psychiatric disorders in which NDMAR hypofunction has been implicated, including schizophrenia. Several modulatory agents targeted at the glycine-B site are currently undergoing pre-clinical and clinical development as potential antipsychotic drugs. Parallel research in animals with pharmacological inhibition of GlyT1 or GlyT1 knock-out mice has also generated promising results, reinforcing the hypothesis that disruption of glycine reuptake via GlyT1 may entail therapeutic value against primarily negative and cognitive symptoms of schizophrenia.
Keywords: Cognitive enhancer, glycine, GlyT1, glutamate, learning and memory, NMDA, schizophrenia
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