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

The GluN2B subunit of N-methyl-D-aspartate receptors (NMDAR) plays a
central role in synaptic development and plasticity, and its hypofunction
is linked to autism spectrum disorder, 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.
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.