Characterization of Mice Carrying a Neurodevelopmental Disease-Associated GluN2B(L825V) Variant

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• N-methyl-D-aspartate receptors (NMDARs), crucial for brain function, are encoded by GRIN genes.
• Variants in GRIN genes are linked to neurodevelopmental disorders, but mechanisms remain unclear.

Purpose of the Study:

• To create and evaluate a mouse model with a Grin2b variant (GluN2B(L825V)) mirroring a human neurodevelopmental disorder.
• To investigate the functional impact of this variant on NMDARs and associated behaviors.

Main Methods:

• Generated a transgenic mouse line with the Grin2b (L825V/+) variant.
• Assessed NMDAR function in HEK293T cells and primary hippocampal neurons using electrophysiology.
• Conducted behavioral testing in heterozygous mice.

Main Results:

• Neurons from L825V/+ mice exhibited reduced whole-cell NMDAR currents and faster deactivation of NMDAR-eEPSCs.
• GluN2B(L825V) variant decreased GluN2B subunit contribution to synaptic NMDAR currents.
• Mice displayed hypoactivity, anxiety, impaired sensorimotor gating, and cognitive deficits, particularly males.

Conclusions:

• The heterozygous L825V/+ mouse is a valid model for GRIN2B-related intellectual disability and autism spectrum disorder.
• Synaptic NMDAR functional changes likely contribute to the observed neurodevelopmental pathology.