RAPID COMMUNICATION Glycine Uptake Governs Glycine Site Occupancy at NMDA Receptors of Excitatory Synapses

Berger, Albert J., Stéphane Dieudonné, and Philippe Ascher. heteromeric NMDA-Rs expressed in Xenopus oocytes and Glycine uptake governs glycine site occupancy at NMDA receptors can reach a few micromolar for other expressed heteromeric of excitatory synapses. J. Neurophysiol. 80: 3336–3340, 1998. At NMDA-Rs (Johnson and Ascher 1992; Mayer et al. 1989; central synapses occupation of glycine binding sites of N-methylMcBain and Mayer 1994; Thomson 1990). As for the extraD-aspartate receptors (NMDA-Rs) is a necessary prerequisite for cellular glycine concentration, it was measured in ‘‘wide’’ the excitatory neurotransmitter glutamate to activate these recepextracellular spaces (sampled by microdialysis) and in ceretors. There is conflicting evidence as to whether glycine binding brospinal fluid. In both it was found to be in the low microsites normally are saturated. If they are not, then alterations in molar range (Kemp and Leeson 1993; Westergren et al. local glycine concentration could modulate excitatory synaptic transmission. By using an in vitro brain stem slice preparation we 1994) and thus could be saturating for some NMDA-Rs and investigated whether the glycine site is saturated for synaptically not for others. However, the concentration of glycine in the activated NMDA-Rs in neonatal rat hypoglossal motoneurons. We synaptic cleft could be much lower if glycine transporters found that the NMDA-R–mediated component of spontaneous (Borowsky et al. 1993; Lukasiewicz and Roeder 1995; Smith miniature excitatory postsynaptic currents could be potentiated by et al. 1992; Zafra et al. 1995) were strategically placed exogenously applied glycine as well as by D-serine. The effects of around the cleft. In rat brain some mRNAs encoding glycine glycine were observed only at concentrations (100 mM or more) transporters are localized to regions that also contain high two orders of magnitude above the apparent dissociation constant levels of NMDA-Rs and low levels of inhibitory glycine of glycine from NMDA receptors. In contrast, D-serine, a nontransreceptors. This suggests that the local glycine concentration ported NMDA-R glycine site agonist, was effective in the low