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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\u2010selective positive allosteric modulator, (+)\u2010EU1180\u2010453, which has improved drug\u2010like properties, such as increased aqueous solubility, in comparison to the first\u2010in\u2010class GluN2C\/GluN2D\u2010selective prototypical positive allosteric modulator, (+)\u2010CIQ. (+)\u2010EU1180\u2010453 doubles the NMDAR response at lower concentrations and produces a greater degree of maximal potentiation at 30 \u00b5M compared with (+)\u2010CIQ. Using\n                      <jats:italic>in vitro<\/jats:italic>\n                      electrophysiological recordings, we show that (+)\u2010EU1180\u2010453 potentiates triheteromeric NMDARs containing at least one GluN2C or GluN2D subunit and is active at both exon5\u2010lacking and exon5\u2010containing GluN1 splice variants. (+)\u2010EU1180\u2010453 increases glutamate efficacy for GluN2C\/GluN2D\u2010containing NMDARs both by prolonging the deactivation time and by potentiating the peak response amplitude. We show that (+)\u2010EU1180\u2010453 selectively increases synaptic NMDAR\u2010mediated charge transfer onto postnatal day 11\u201315 CA1\n                      <jats:italic>stratum radiatum<\/jats:italic>\n                      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\u2010dependent manner. (+)\u2010EU1180\u2010453 also shifts excitatory\u2010to\u2010inhibitory coupling towards increased inhibition and produces enhanced gamma\u2010band power from carbachol\u2010induced field potential oscillations in hippocampal slices. Thus, (+)\u2010EU1180\u2010453 can enhance overall circuit inhibition, which could prove therapeutically useful for the treatment of anxiety, depression, schizophrenia and other neuropsychiatric disorders.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16817-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>(+)EU\u20101180\u2010453 is a GluN2C\/GluN2D positive allosteric modulator and is active at triheteromeric receptors.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>(+)EU\u20101180\u2010453 is active at exon5\u2010containing and exon5\u2010lacking GluN1\u2010containing receptors.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>(+)EU\u20101180\u2010453 selectively potentiates the interneuron network and can enhance carbachol\u2010induced gamma\u2010band power.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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