GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour

Ester Francija, Iva Lukic, Zorica Petrovic, Zeljka Brkic, Milos Mitic, Jelena Radulovic, Miroslav Adzic

Research output: Contribution to journalArticlepeer-review

Abstract

Inflammation plays a key role in the pathogenesis of the major depressive disorder. Namely, neuroinflammation can induce the production of neuroactive metabolites that interfere with N-methyl-D-aspartate receptors (NMDAR)-mediated glutamatergic neurotransmission and contribute to depressive-like behaviour. On the other hand, mammalian target of rapamycin (mTOR) activity with synaptogenic effects is the main mediator of antidepressant effects of several potent NMDAR antagonists. In this study, we investigated the specific role of GluN2A subunits of NMDAR on the activity of mTOR signaling and behaviour in lipopolysaccharide (LPS)-induces model of depression. The results showed that mice lacking GluN2A subunit did not display depressive-like behavior after the immune challenge, opposite to LPS-treated wild-type mice. Specifically, in GluN2A knockout mice, we estimated the activity of the mTOR pathway in the hippocampus and prefrontal cortex (PFC) by measuring synaptic levels of upstream regulators (p-Akt, p-ERK, and p-GSK3β) and downstream effectors (p-mTOR, and p-p70S6K) of mTOR activity. In addition, we assessed the changes in the levels of two important synaptic markers, GluA1 and PSD-95. Contrary to downregulated mTOR signaling and decreased synaptic markers in LPS-treated wild-type animals, the resilience of GluN2A KO mice to depressive-like behaviour was paralleled with sustained mTOR signaling activity synaptic stability in hippocampus and PFC. Finally, we disclosed that resistance of GluN2A knockouts to LPS-induced depressive-like behavior was ERK-dependent. These findings demonstrate that GluN2A-ERK-mTOR signaling is a vulnerability factor of inflammation-related depressive behaviour, making this signaling pathway the promising target for developing novel antidepressants.

Original languageEnglish (US)
Article number113625
JournalBehavioural Brain Research
Volume417
DOIs
StatePublished - Jan 24 2022

Keywords

  • GluN2A knockout mice
  • Glutamatergic neurotransmission
  • LPS-induced depression
  • Synaptosomes
  • mTOR signaling

ASJC Scopus subject areas

  • Behavioral Neuroscience

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