Characterization of mice carrying an autism-related point mutation in the NMDA receptor subunit gene Grin2b

Abstract

The GRIN2B gene, which encodes the GluN2B subunit of NMDA receptors (NMDARs), is one of the most frequently mutated genes in autism spectrum disorders (ASDs) patients. However, how such mutations in GRIN2B lead to ASDs are not clearly understood. Here we show that a point mutation of GRIN2B identified in autistic individuals (C456Y) lead to a complete degradation of the GluN2B protein by disrupting the disulfide-bond interaction of the two major extracellular domains (amino terminal and ligand binding). Heterozygous mice carrying this mutation ($Grin2b^{+/C456Y}$) show reduced function of GluN2B-containing NMDARs and NMDAR-dependent long-term depression but normal long-term potentiation. Behaviorally, unstimulated $Grin2b^{+/C456Y}$ mice are largely normal except for moderate anxiolytic-like behaviors, but, when exposed to fearful stimuli such as separation from mothers and fear-conditioning shocks, show exaggerated fear responses anxiety state. These behaviors are thought to be associated with abnormally enhanced excitatory drive in the cortex and inhibitory drive in the amygdala under basal conditions. These results suggest that the ASD-risk point mutation of GRIN2B leads to complete protein degradation, specific suppression of long-term depression, excessive brain excitation, and exaggerated responses to fearful stimuli.