N-Methyl-d-aspartate receptors (NMDARs) are a family of ligand-gated ionotropic glutamate receptors that mediate a slow, calcium-permeable component to excitatory neurotransmission. The GluN2D subunit is enriched in GABAergic inhibitory interneurons in cortical tissue. Diminished levels of GABAergic inhibition contribute to multiple neuropsychiatric conditions, suggesting that enhancing inhibition might have therapeutic utility, thus making GluN2D modulation an attractive drug target. Here, we describe the actions of a GluN2C/GluN2D-selective positive allosteric modulator, (+)-EU1180-453, which has improved drug-like properties, such as increased aqueous solubility, in comparison to the first-in-class GluN2C/GluN2D-selective prototypical positive allosteric modulator, (+)-CIQ. (+)-EU1180-453 doubles the NMDAR response at lower concentrations and produces a greater degree of maximal potentiation at 30 µM compared with (+)-CIQ. Using in vitro electrophysiological recordings, we show that (+)-EU1180-453 potentiates triheteromeric NMDARs containing at least one GluN2C or GluN2D subunit and is active at both exon5-lacking and exon5-containing GluN1 splice variants. (+)-EU1180-453 increases glutamate efficacy for GluN2C/GluN2D-containing NMDARs both by prolonging the deactivation time and by potentiating the peak response amplitude. We show that (+)-EU1180-453 selectively increases synaptic NMDAR-mediated charge transfer onto postnatal day 11-15 CA1 stratum radiatum hippocampal interneurons but is without effect on CA1 pyramidal cells. This increased charge transfer enhances inhibitory output from GABAergic interneurons onto CA1 pyramidal cells in a GluN2D-dependent manner. (+)-EU1180-453 also shifts excitatory-to-inhibitory coupling towards increased inhibition and produces enhanced gamma-band power from carbachol-induced field potential oscillations in hippocampal slices. Thus, (+)-EU1180-453 can enhance overall circuit inhibition, which could prove therapeutically useful for the treatment of anxiety, depression, schizophrenia and other neuropsychiatric disorders. KEY POINTS: (+)EU-1180-453 is a GluN2C/GluN2D positive allosteric modulator and is active at triheteromeric receptors. (+)EU-1180-453 is active at exon5-containing and exon5-lacking GluN1-containing receptors. (+)EU-1180-453 selectively potentiates the interneuron network and can enhance carbachol-induced gamma-band power.
