Johnson and Ascher first demonstrated that,in the vertebrate central nervous system (CNS),exogenously applied glycine potentiates the response of N-methyl-D-aspartate receptors (NMDA-Rs) to NMDA.Binding of glycine to the glycine binding site of NMDA-Rs is a pre-requirement for NMDA-R activation by glutamate.Thus,glycine and glutamate are co-agonists for NMDA-Rs.It is generally assumed that the glycine binding site is constantly saturated due to high concentrations of glycine in cerebrospinal fluid (CSF).However,glycine in the synaptic cleft is subject to a powerful uptake system (i.e.,glycine transporter 1 and 2,GlyT1 and GlyT2).In addition,NMDA-R isoforms exhibit different affinities to glycine.A surge of in vivo and in vitro studies have suggested that saturation of the glycine binding varies among different brain areas.Some studies have shown that the application of exogenous glycine increases NMDA-R responses,while others have found no modulatory effect.To date,a number of studies have shown that the NMDA-Rs are present on the presynaptic membrane in addition to the postsynaptic area.Presynaptic NMDA-Rs have been found to enhance neurotransmitter release in different regions of the CNS including the spinal cord,cerebellum,entorhinal cortex,and neocortex.