TY  - JOUR
AU  - Francija, Ester
AU  - Lukić, Iva
AU  - Petrović, Zorica
AU  - Brkić, Željka
AU  - Mitić, Miloš
AU  - Radulović, Jelena
AU  - Adžić, Miroslav
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10580
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-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.
T2  - Behavioural Brain Research
T1  - GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour
VL  - 417
SP  - 113625
DO  - 10.1016/j.bbr.2021.113625
ER  - 

@article{
author = "Francija, Ester and Lukić, Iva and Petrović, Zorica and Brkić, Željka and Mitić, Miloš and Radulović, Jelena and Adžić, Miroslav",
year = "2022",
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.",
journal = "Behavioural Brain Research",
title = "GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour",
volume = "417",
pages = "113625",
doi = "10.1016/j.bbr.2021.113625"
}

Francija, E., Lukić, I., Petrović, Z., Brkić, Ž., Mitić, M., Radulović, J.,& Adžić, M.. (2022). GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour. in Behavioural Brain Research, 417, 113625.
https://doi.org/10.1016/j.bbr.2021.113625

Francija E, Lukić I, Petrović Z, Brkić Ž, Mitić M, Radulović J, Adžić M. GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour. in Behavioural Brain Research. 2022;417:113625.
doi:10.1016/j.bbr.2021.113625 .

Francija, Ester, Lukić, Iva, Petrović, Zorica, Brkić, Željka, Mitić, Miloš, Radulović, Jelena, Adžić, Miroslav, "GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour" in Behavioural Brain Research, 417 (2022):113625,
https://doi.org/10.1016/j.bbr.2021.113625 . .

TY  - JOUR
AU  - Aleksić, Minja
AU  - Brkić, Željka
AU  - Petrović, Zorica
AU  - Francija, Ester
AU  - Lukić, Iva
AU  - Adžić, Miroslav
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10579
AB  - Adolescent stress predisposes individuals to increased risk for anxiety and depression in adulthood. The stress response is mediated by the glucocorticoid receptor (GR) via regulation of GR-responsive genes involved in brain reaction to stress. Although dysregulation of GR in depression is well documented, this is the first study investigating the role of GRα isoforms in pathogenesis of depression. We exposed adolescent male and female C57BL/6J mice to chronic unpredictable stress (CUS) for 12 days starting at postnatal day 28 (PND28). Tests evaluating anxiety and depressive-like behaviors were performed at PND70. We analyzed corticosterone concentrations in serum, levels of GRα isoforms (95, 67, 50, 40, and 25 kDa), and mRNA levels of GR-responsive genes (GR, FKBP5, BDNF, and IL-1β) in the hippocampus and the prefrontal cortex (PFC). CUS increased anxiety and depressive-like behavior in adult animals of both sexes, but did not affect corticosterone serum levels, 95 and 67 kDa GR isoforms. However, the levels of shorter GRα isoforms (50, 40, and 25 kDa) were altered in adult mice underwent CUS, in sex- and brain structure–specific way. Changes in gene expression revealed that female depressive-like behavior could be related to increased levels of IL-1β in hippocampus and reduced BDNF levels in both hippocampus and PFC. However, in males, adolescent CUS increased expression of GR in adult hippocampus and BDNF in PFC. These findings suggest that adolescent stress altered levels of GRα isoforms, especially those with lower molecular weight, in sex- and tissue-specific ways, contributing to anxiety and depression in adult mice.
T2  - Journal of Neuroscience Research
T1  - Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice
VL  - 100
IS  - 5
SP  - 1239
EP  - 1253
DO  - 10.1002/jnr.25032
ER  - 

@article{
author = "Aleksić, Minja and Brkić, Željka and Petrović, Zorica and Francija, Ester and Lukić, Iva and Adžić, Miroslav",
year = "2022",
abstract = "Adolescent stress predisposes individuals to increased risk for anxiety and depression in adulthood. The stress response is mediated by the glucocorticoid receptor (GR) via regulation of GR-responsive genes involved in brain reaction to stress. Although dysregulation of GR in depression is well documented, this is the first study investigating the role of GRα isoforms in pathogenesis of depression. We exposed adolescent male and female C57BL/6J mice to chronic unpredictable stress (CUS) for 12 days starting at postnatal day 28 (PND28). Tests evaluating anxiety and depressive-like behaviors were performed at PND70. We analyzed corticosterone concentrations in serum, levels of GRα isoforms (95, 67, 50, 40, and 25 kDa), and mRNA levels of GR-responsive genes (GR, FKBP5, BDNF, and IL-1β) in the hippocampus and the prefrontal cortex (PFC). CUS increased anxiety and depressive-like behavior in adult animals of both sexes, but did not affect corticosterone serum levels, 95 and 67 kDa GR isoforms. However, the levels of shorter GRα isoforms (50, 40, and 25 kDa) were altered in adult mice underwent CUS, in sex- and brain structure–specific way. Changes in gene expression revealed that female depressive-like behavior could be related to increased levels of IL-1β in hippocampus and reduced BDNF levels in both hippocampus and PFC. However, in males, adolescent CUS increased expression of GR in adult hippocampus and BDNF in PFC. These findings suggest that adolescent stress altered levels of GRα isoforms, especially those with lower molecular weight, in sex- and tissue-specific ways, contributing to anxiety and depression in adult mice.",
journal = "Journal of Neuroscience Research",
title = "Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice",
volume = "100",
number = "5",
pages = "1239-1253",
doi = "10.1002/jnr.25032"
}

Aleksić, M., Brkić, Ž., Petrović, Z., Francija, E., Lukić, I.,& Adžić, M.. (2022). Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice. in Journal of Neuroscience Research, 100(5), 1239-1253.
https://doi.org/10.1002/jnr.25032

Aleksić M, Brkić Ž, Petrović Z, Francija E, Lukić I, Adžić M. Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice. in Journal of Neuroscience Research. 2022;100(5):1239-1253.
doi:10.1002/jnr.25032 .

Aleksić, Minja, Brkić, Željka, Petrović, Zorica, Francija, Ester, Lukić, Iva, Adžić, Miroslav, "Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice" in Journal of Neuroscience Research, 100, no. 5 (2022):1239-1253,
https://doi.org/10.1002/jnr.25032 . .