GluN2B-specific NMDAR positive allosteric modulation reverses cognitive and behavioral abnormalities in <i>Mecp2</i> and <i>Disc1</i> transgenic mice

The GluN2B subunit of <i>N</i>-methyl-d-aspartate receptors (NMDARs) plays a central role in synaptic development and plasticity, and its hypofunction is linked to autism spectrum disorder (ASD), severe neurodevelopmental delay, and other neuropsychiatric diseases. Therefore, enhancing the function of this NMDAR subunit may provide an effective therapeutic strategy for correcting synaptic and behavioral deficits associated with GluN2B hypofunction. Here, we developed a class of GluN2B-selective positive allosteric modulators and characterized the pharmacological properties and binding site of the lead compound, 175. Systemic application of 175 facilitates hippocampal long-term depression in rats. 175 restores performances in open-field exploration and three-chamber test in <i>Mecp2</i> overexpression mice that exhibit GluN2B hypofunction and autism-like features. Treatment with 175 also reverses behavioral abnormalities in open-field, Y-maze spontaneous alternation, three-chamber test, and prepulse inhibition in <i>Disc1</i> mutant mice. Our findings introduce a pharmacological tool for selectively potentiating GluN2B-NMDAR function and highlight its therapeutic potential for cognitive and behavioral symptoms associated with GluN2B hypofunction.