Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes

Background and purpose Astrocytes of the mouse neocortex express functional NMDA receptors which are not blocked by Mg2+ions. However, study of the pharmacological profile of glial NMDARs and their subunit composition is far from complete. Experimental approach In the present study we tested the sensitivity of NMDA receptor-mediated currents in the cortical astrocytes and neurons to the novel GluN2C/D subunit-selective antagonist UBP141. We also examined the action of memantine, an antagonist reported to have substantially different affinities for GluN2A/B and GluN2C/D-containing receptors in physiological concentrations of extracellular Mg2+ . Key results UBP141 had a strong inhibitory action on NMDA receptor-mediated transmembrane currents in the cortical layer II/III astrocytes with an IC50 of 2.29 μM and a modest inhibitory action on NMDA-responses in the pyramidal neurons with IC50 of 19.8 μM. Astroglial and neuronal NMDA receptors exhibited different sensitivities to memantine with corresponding IC50 of 2.19 and 10.8 μM, respectively. Consistent with pharmacological differences between astroglial and neuronal NMDA receptors, NMDA receptors in astrocytes showed lower Ca2+-permeability than neuronal ones with PCa/PNa ratio of 3.4. Conclusions and Implications The combination of biophysical and pharmacological properties of astrocytic NMDA receptors strongly suggests they have tri-heteromeric structure composed of GluN1, GluN2C/D and GluN3 subunits. Dramatic difference between astroglial and neuronal NMDA receptors in their sensitivity to UBP141 and memantine may enable selective modulation of astrocytic signalling that could be very helpful for elucidating the mechanisms of neuron-glia communications. Our results may also provide a clue for development novel therapeutic agents specifically targeting glial signalling