Enhancement of the NMDA receptor function by reduction of glycine transporter-1 expression

The occupation of the glycine binding-site is a prerequisite for NMDA receptor activation by glutamate. To analyze the regulation of NMDA receptor function by the glycine transporter 1 (GlyT1), we generated heterozygous constitutive GlyT1 knockout mice (GlyT1tm1.1(+/-)). These animals were fully viable. Using a newly generated antibody, the pattern of GlyT1 expression in brain was found to be unaltered in the mutants while the level of expression was strongly reduced in all brain regions, as shown immunohistochemically. In hippocampal slices the ratio of the peak amplitude of NMDA and AMPA receptor evoked excitatory postsynaptic currents (EPSCs), recorded in CA1 pyramidal cells, was significantly enhanced by 36% in Glyt1tm1.1(+/-) compared to wild-type slices. The frequency and amplitude of AMPA miniature events in Glyt1tm1.1(+/-) mice were indistinguishable from those recorded in wild type. These results provide proof that the NMDA receptor function is enhanced by a reduction of GlyT1 expression. Thus, GlyT1 function is a controlling factor for an enhancement of the NMDA receptor response. These findings are of relevance for the development of GlyT1 inhibitory drugs.