Cell reports (Cambridge), 2021-08, Vol.36 (8), p.109612-109612, Article 109612
2021
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- Autor(en) / Beteiligte
- Titel
- Disrupting phosphorylation of Tyr-1070 at GluN2B selectively produces resilience to depression-like behaviors
- Ist Teil von
- Cell reports (Cambridge), 2021-08, Vol.36 (8), p.109612-109612, Article 109612
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Drugs targeting N-methyl-D-aspartate receptors (NMDARs) have been approved to treat major depressive disorder (MDD); however, the presence of undesirable psychotomimetic and cognitive side effects may limit their utility. In this study, we show that the phosphorylation levels of the GluN2B subunit at tyrosine (Y) 1070 increase in mice after both acute and chronic restraint stress (CRS) exposure. Preventing GluN2B-Y1070 phosphorylation via Y1070F mutation knockin produces effects similar to those of antidepressants but does not affect cognitive or anxiety-related behaviors in subject mice. Mechanistically, the Y1070F mutation selectively reduces non-synaptic NMDAR currents and increases the number of excitatory synapses in the layer 5 pyramidal neurons of medial prefrontal cortex (mPFC) but not in the hippocampus. Altogether, our study identifies phosphorylation levels of GluN2B-Y1070 in the mPFC as a dynamic, master switch guarding depressive behaviors, suggesting that disrupting the Y1070 phosphorylation of GluN2B subunit has the potential for developing new antidepressants. [Display omitted] •GluN2B-Y1070F mice selectively display antidepressant-like behaviors•Deleting GluN2B-Y1070 phosphorylation causes non-synaptic NMDARs hypofunction in mPFC•Deleting GluN2B-Y1070 phosphorylation promotes mTOR-dependent synaptogenesis in mPFC•Deleting GluN2B-Y1070 phosphorylation reduces CRS-induced depressive-like behaviors Shi et al. show that GluN2B-Y1070F mice exhibit antidepressant-like behaviors by suppressing the function of non-synaptic NMDARs in mPFC layer 5 pyramidal neurons, which facilitates mTOR-dependent synaptogenesis. Our results indicate that the dynamic regulation of tyrosine phosphorylation of GluN2B in mPFC is critical for the pathogenesis of depressive symptoms.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2211-1247eISSN: 2211-1247DOI: 10.1016/j.celrep.2021.109612Titel-ID: cdi_doaj_primary_oai_doaj_org_article_c34ec88cefe945bc8bf67a7d6a835725
- Format
- –
- Schlagworte
- Animals, Antidepressive Agents - pharmacology, Behavior, Animal - drug effects, depression, Depression - drug therapy, Depressive Disorder, Major - drug therapy, Depressive Disorder, Major - metabolism, GluN2B Y1070, Hippocampus - drug effects, Hippocampus - metabolism, Mice, mPFC region, Neurons - metabolism, non-synaptic NMDARs, Receptors, N-Methyl-D-Aspartate - drug effects, Receptors, N-Methyl-D-Aspartate - metabolism, Synapses - drug effects, Synapses - metabolism, Tyrosine - drug effects, Tyrosine - metabolism, tyrosine phosphorylation