GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour
| Autor: | Milos Mitic, Jelena Radulovic, Zorica Petrovic, Iva Lukic, Zeljka Brkic, Miroslav Adzic, Ester Francija |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
Lipopolysaccharides Male Hippocampus Prefrontal Cortex Neurotransmission Biology Receptors N-Methyl-D-Aspartate Article 03 medical and health sciences Behavioral Neuroscience Mice 0302 clinical medicine Animals GluN2A knockout mice Glutamatergic neurotransmission Neuroinflammation PI3K/AKT/mTOR pathway 030304 developmental biology Mice Knockout 0303 health sciences Depression TOR Serine-Threonine Kinases LPS-induced depression Cell biology Knockout mouse mTOR signaling NMDA receptor Signal transduction Disks Large Homolog 4 Protein 030217 neurology & neurosurgery Synaptosomes Signal Transduction |
| Zdroj: | Behav Brain Res Behavioural Brain Research |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|