PMID- 34637854 OWN - NLM STAT- MEDLINE DCOM- 20220318 LR - 20230127 IS - 1872-7549 (Electronic) IS - 0166-4328 (Print) IS - 0166-4328 (Linking) VI - 417 DP - 2022 Jan 24 TI - GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour. PG - 113625 LID - S0166-4328(21)00513-1 [pii] LID - 10.1016/j.bbr.2021.113625 [doi] AB - 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-GSK3beta) 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. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Francija, Ester AU - Francija E AD - Department of Molecular Biology and Endocrinology, "VINCA" Institute of Nuclear Sciences - National Institute of thsmall ie, Cyrillic Republic of Serbia, University of Belgrade, Belgrade. FAU - Lukic, Iva AU - Lukic I AD - Department of Molecular Biology and Endocrinology, "VINCA" Institute of Nuclear Sciences - National Institute of thsmall ie, Cyrillic Republic of Serbia, University of Belgrade, Belgrade. FAU - Petrovic, Zorica AU - Petrovic Z AD - Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Brkic, Zeljka AU - Brkic Z AD - Department of Molecular Biology and Endocrinology, "VINCA" Institute of Nuclear Sciences - National Institute of thsmall ie, Cyrillic Republic of Serbia, University of Belgrade, Belgrade. FAU - Mitic, Milos AU - Mitic M AD - Department of Molecular Biology and Endocrinology, "VINCA" Institute of Nuclear Sciences - National Institute of thsmall ie, Cyrillic Republic of Serbia, University of Belgrade, Belgrade. FAU - Radulovic, Jelena AU - Radulovic J AD - Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA. FAU - Adzic, Miroslav AU - Adzic M AD - Department of Molecular Biology and Endocrinology, "VINCA" Institute of Nuclear Sciences - National Institute of thsmall ie, Cyrillic Republic of Serbia, University of Belgrade, Belgrade. Electronic address: miraz@vinca.rs. LA - eng GR - R01 MH078064/MH/NIMH NIH HHS/United States GR - R21 MH098793/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20211009 PL - Netherlands TA - Behav Brain Res JT - Behavioural brain research JID - 8004872 RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Lipopolysaccharides) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - VH92ICR8HX (N-methyl D-aspartate receptor subtype 2A) SB - IM MH - Animals MH - Depression/chemically induced/*metabolism MH - Disks Large Homolog 4 Protein/*metabolism MH - Hippocampus/*metabolism MH - Lipopolysaccharides/*pharmacology MH - Male MH - Mice MH - Mice, Knockout MH - Prefrontal Cortex/metabolism MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases PMC - PMC9878822 MID - NIHMS1748017 OTO - NOTNLM OT - GluN2A knockout mice OT - Glutamatergic neurotransmission OT - LPS-induced depression OT - Synaptosomes OT - mTOR signaling COIS- Conflict of interest The authors declare no conflict of interest. EDAT- 2021/10/13 06:00 MHDA- 2022/03/19 06:00 PMCR- 2023/01/26 CRDT- 2021/10/12 20:15 PHST- 2021/06/23 00:00 [received] PHST- 2021/09/28 00:00 [revised] PHST- 2021/10/06 00:00 [accepted] PHST- 2021/10/13 06:00 [pubmed] PHST- 2022/03/19 06:00 [medline] PHST- 2021/10/12 20:15 [entrez] PHST- 2023/01/26 00:00 [pmc-release] AID - S0166-4328(21)00513-1 [pii] AID - 10.1016/j.bbr.2021.113625 [doi] PST - ppublish SO - Behav Brain Res. 2022 Jan 24;417:113625. doi: 10.1016/j.bbr.2021.113625. Epub 2021 Oct 9.