Journal Article

Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice

Paoletti, Pierre, Kim, Kyungdeok, Serraz, Benjamin, Kim, Doyoun, Lee, Hyejin, Bae, Yong Chul, Kim, Eunjoon, Cho, Yi Sul, Shin, Wangyong, Kang, Muwon, Lee, Eun-Jae

2020

Overview

Extensive evidence links Glutamate receptor, ionotropic, NMDA2B (GRIN2B), encoding the GluN2B/NR2B subunit of N-methyl-D-aspartate receptors (NMDARs), with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), but the underlying mechanisms remain unclear. In addition, it remains unknown whether mutations in GluN2B, which starts to be expressed early in development, induces early pathophysiology that can be corrected by early treatments for long-lasting effects. We generated and characterized Grin2b-mutant mice that carry a heterozygous, ASD-risk C456Y mutation (Grin2b+/C456Y). In Grin2b+/C456Y mice, GluN2B protein levels were strongly reduced in association with decreased hippocampal NMDAR currents and NMDAR-dependent long-term depression (LTD) but unaltered long-term potentiation, indicative of mutation-induced protein degradation and LTD sensitivity. Behaviorally, Grin2b+/C456Y mice showed normal social interaction but exhibited abnormal anxiolytic-like behavior. Importantly, early, but not late, treatment of young Grin2b+/C456Y mice with the NMDAR agonist D-cycloserine rescued NMDAR currents and LTD in juvenile mice and improved anxiolytic-like behavior in adult mice. Therefore, GluN2B-C456Y haploinsufficiency decreases GluN2B protein levels, NMDAR-dependent LTD, and anxiety-like behavior, and early activation of NMDAR function has long-lasting effects on adult mouse behavior.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Anxiety / Anxiolytics / Autism / Behavior / Biodegradation / Biology and Life Sciences / Care and treatment / Cell receptors / Chemical bonds / Cycloserine / Dentistry / Disorders / Genes / Glutamate receptors / Glutamic acid receptors / Haploinsufficiency / Hippocampus / Intellectual disabilities / Investigations / Life Sciences / Long-term depression / Long-term potentiation / Medicine and Health Sciences / Mental depression / Methyl aspartate / Mutants / Mutation / N-Methyl-D-aspartic acid receptors / Neurobiology / Neurodevelopmental disorders / Neurons and Cognition / Neurosciences / Physiological aspects / Proteins / Psychology and behavior / Receptors / Research and Analysis Methods / Social behavior / Social factors / Social Sciences / Supervision / Synapses