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

Ester Francija1, Iva Lukic1, Zorica Petrovic2

  • 1Department of Molecular Biology and Endocrinology, "VINČA" Institute of Nuclear Sciences - National Institute of thе Republic of Serbia, University of Belgrade, Belgrade.

Behavioural Brain Research
|October 12, 2021
PubMed

Insights

Mice lacking the GluN2A subunit of N-methyl-D-aspartate receptors (NMDAR) resist depression-like behaviors induced by inflammation. This resilience is linked to sustained mTOR signaling, highlighting GluN2A-ERK-mTOR pathways as potential antidepressant targets.

Area of Science:

  • Neuroscience
  • Molecular Psychiatry
  • Immunology

Background:

  • Inflammation and neuroinflammation are implicated in major depressive disorder (MDD) pathogenesis.
  • Neuroinflammation disrupts N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission, contributing to depressive behaviors.
  • Mammalian target of rapamycin (mTOR) signaling, with its synaptogenic effects, mediates antidepressant actions of NMDAR antagonists.

Purpose of the Study:

  • To investigate the role of GluN2A subunits of NMDAR in modulating mTOR signaling and behavior within a lipopolysaccharide (LPS)-induced mouse model of depression.
  • To elucidate the specific contribution of GluN2A to inflammation-induced depressive-like behaviors and associated molecular changes.

Main Methods:

  • Utilized a lipopolysaccharide (LPS)-induced mouse model to mimic inflammation-related depression.
  • Compared depressive-like behaviors and molecular signaling in wild-type (WT) mice and GluN2A knockout (KO) mice.
  • Assessed mTOR pathway activity in the hippocampus and prefrontal cortex (PFC) by measuring levels of key signaling proteins (p-Akt, p-ERK, p-GSK3β, p-mTOR, p-p70S6K).
  • Quantified synaptic markers, including GluA1 and PSD-95, to evaluate synaptic integrity.

Main Results:

  • LPS administration induced depressive-like behaviors in WT mice but not in GluN2A KO mice.
  • LPS-treated WT mice exhibited downregulated mTOR signaling and reduced synaptic markers (GluA1, PSD-95) in the hippocampus and PFC.
  • GluN2A KO mice showed sustained mTOR signaling activity and synaptic stability, correlating with their resilience to depressive behaviors.
  • The resistance of GluN2A KO mice to LPS-induced depression was found to be dependent on ERK signaling.

Conclusions:

  • The GluN2A subunit of NMDAR is a critical factor in the vulnerability to inflammation-related depressive behaviors.
  • The GluN2A-ERK-mTOR signaling pathway plays a significant role in the pathogenesis of depression induced by immune challenges.
  • Targeting the GluN2A-ERK-mTOR pathway offers a promising strategy for the development of novel antidepressant therapies for inflammation-associated depression.
Keywords:
GluN2A knockout miceGlutamatergic neurotransmissionLPS-induced depressionSynaptosomesmTOR signaling

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