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

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. Importantly, 175 restores performances in open-field exploration and three-chamber test in Mecp2 overexpression mice.

Treatment with 175 also reverses behavioral abnormalities in open-field, Y-maze spontaneous alternation, three-chamber test, and pre-pulse inhibition in Disc1 mutant mice. Our findings introduce a pharmacological tool for selectively potentiating GluN2B-NMDARs function and highlight its therapeutic potential for cognitive and behavioral symptoms associated with GluN2B hypofunction.