Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice.
Animals
Anxiety
/ genetics
Behavior, Animal
/ drug effects
Cycloserine
/ pharmacology
Excitatory Postsynaptic Potentials
/ genetics
Gene Knock-In Techniques
Haploinsufficiency
/ genetics
Heterozygote
Hippocampus
/ metabolism
Long-Term Synaptic Depression
/ drug effects
Mice, Mutant Strains
Mutation
Nerve Tissue Proteins
/ metabolism
Receptors, N-Methyl-D-Aspartate
/ agonists
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
24
02
2020
accepted:
15
04
2020
revised:
12
05
2020
pubmed:
1
5
2020
medline:
28
7
2020
entrez:
1
5
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32353004
doi: 10.1371/journal.pbio.3000717
pii: PBIOLOGY-D-20-00469
pmc: PMC7217483
doi:
Substances chimiques
Gprin1 protein, mouse
0
NR2B NMDA receptor
0
Nerve Tissue Proteins
0
Receptors, N-Methyl-D-Aspartate
0
Cycloserine
95IK5KI84Z
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3000717Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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