Disrupting phosphorylation of Tyr-1070 at GluN2B selectively produces resilience to depression-like behaviors.
Cell Rep
; 36(8): 109612, 2021 08 24.
Article
in En
| MEDLINE
| ID: mdl-34433031
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tyrosine
/
Behavior, Animal
/
Depression
/
Antidepressive Agents
Limits:
Animals
Language:
En
Journal:
Cell Rep
Year:
2021
Document type:
Article