2. Academic Validation
  3. GluN2B-specific NMDAR positive allosteric modulation reverses cognitive and behavioral abnormalities in Mecp2 and Disc1 transgenic mice

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

  • Sci Adv. 2026 Jan 9;12(2):eady3891. doi: 10.1126/sciadv.ady3891.
Yang Ge 1,  Tian Tian 2 3,  Bolong Li 2 3 4,  Peter Axerio-Cillies 1,  Wenlin Chen 1 2 3 4,  Xin Qin 1,  Mudi Zhao 1,  Qi-Cheng Sun 5,  Jiaqi Li 1,  Stan B Floresco 1,  Lidong Liu 1,  Xin Yang 2 3 4,  Yu Tian Wang 1 2 3 4
Affiliations

Affiliations

  • 1 Djavad Mowafaghian Centre for Brain Health and Department of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
  • 2 Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Shenzhen, PR China.
  • 3 Shenzhen Key Laboratory of Translational Research for Brain Diseases, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, PR China.
  • 4 Fudan-SANS Neuroscience Center, Fudan University, Shanghai, PR China.
  • 5 School of Finance, Southwestern University of Finance and Economics, Chengdu, PR China.
PMID: 41512078 DOI: 10.1126/sciadv.ady3891
Abstract

The GluN2B subunit of N-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 Mecp2 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 Disc1 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.

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