TY  - CONF
AU  - Glavonić, Emilija
AU  - Aleksić, Minja
AU  - Francija, Ester
AU  - Mitić, Miloš
AU  - Lukić, Iva
AU  - Ivković, Sanja
AU  - Adžić, Miroslav
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11051
AB  - Adolescence is a developmental stage characterized by impaired fear extinction learning, which is a significant contributing factor for the high incidence of fearrelated disorders observed across this period. Ketamine is a noncompetitive N-methyl D-aspartate receptor antagonist that targets glutamatergic transmission and mammalian target of rapamycin (mTOR) signaling pathway, synaptic plasticity mediators known to be involved in fear extinction processes. Therefore, we aimed to explore ketamine’s potential to boost fear extinction of adolescent males, as well as to identify the associated molecular mechanisms. Adolescent male mice (C57BL/6) received an i.p. ketamine injection (10 mg/kg) 1h prior to each cued fear extinction session for 4 consecutive days. Protein expression levels of synaptic plasticity markers in hippocampal synaptosomal fractions were subsequently detected by Western blot analysis. Our results revealed that ketamine significantly improved overall fear extinction learning, as well as extinction memory consolidation/retention. Our data also showed that ketamine upregulated protein kinase B (Akt), mTOR and glutamate receptor 1 (GluR1) protein levels in the hippocampus. Interestingly, we detected no changes in the levels of extracellular signal-regulated kinase 1/2. These results suggest that ketamine ameliorates longterm fear extinction of adolescent males via hippocampal Akt-mTOR-GluR1 signaling, highlighting this pathway as an important therapeutic target for improving extinction learning in the adolescent population.
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling
SP  - 82
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11051
ER  - 

@conference{
author = "Glavonić, Emilija and Aleksić, Minja and Francija, Ester and Mitić, Miloš and Lukić, Iva and Ivković, Sanja and Adžić, Miroslav",
year = "2023",
abstract = "Adolescence is a developmental stage characterized by impaired fear extinction learning, which is a significant contributing factor for the high incidence of fearrelated disorders observed across this period. Ketamine is a noncompetitive N-methyl D-aspartate receptor antagonist that targets glutamatergic transmission and mammalian target of rapamycin (mTOR) signaling pathway, synaptic plasticity mediators known to be involved in fear extinction processes. Therefore, we aimed to explore ketamine’s potential to boost fear extinction of adolescent males, as well as to identify the associated molecular mechanisms. Adolescent male mice (C57BL/6) received an i.p. ketamine injection (10 mg/kg) 1h prior to each cued fear extinction session for 4 consecutive days. Protein expression levels of synaptic plasticity markers in hippocampal synaptosomal fractions were subsequently detected by Western blot analysis. Our results revealed that ketamine significantly improved overall fear extinction learning, as well as extinction memory consolidation/retention. Our data also showed that ketamine upregulated protein kinase B (Akt), mTOR and glutamate receptor 1 (GluR1) protein levels in the hippocampus. Interestingly, we detected no changes in the levels of extracellular signal-regulated kinase 1/2. These results suggest that ketamine ameliorates longterm fear extinction of adolescent males via hippocampal Akt-mTOR-GluR1 signaling, highlighting this pathway as an important therapeutic target for improving extinction learning in the adolescent population.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling",
pages = "82",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11051"
}

Glavonić, E., Aleksić, M., Francija, E., Mitić, M., Lukić, I., Ivković, S.,& Adžić, M.. (2023). Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neuroscience Society., 82.
https://hdl.handle.net/21.15107/rcub_vinar_11051

Glavonić E, Aleksić M, Francija E, Mitić M, Lukić I, Ivković S, Adžić M. Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:82.
https://hdl.handle.net/21.15107/rcub_vinar_11051 .

Glavonić, Emilija, Aleksić, Minja, Francija, Ester, Mitić, Miloš, Lukić, Iva, Ivković, Sanja, Adžić, Miroslav, "Ketamine ameliorates fear extinction learning in adolescent males via hippocampal mTOR signaling" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):82,
https://hdl.handle.net/21.15107/rcub_vinar_11051 .

TY  - JOUR
AU  - Glavonić, Emilija
AU  - Mitić, Miloš
AU  - Francija, Ester
AU  - Petrović, Zorica
AU  - Adžić, Miroslav
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10514
AB  - Adolescence is a key phase of development for perturbations in fear extinction, with inability to adequately manage fear a potent factor for developing psychiatric disorders in adulthood. However, while behavioral correlates of adolescent fear regulation are established to a degree, molecular mediators of extinction learning in adolescence remain largely unknown. In this study, we observed fear acquisition and fear extinction (across 4 and 7 days) of adolescent and adult mice of both sexes and investigated how hippocampal levels of different plasticity markers relate to extinction learning. While fear was acquired evenly in males and females of both ages, fear extinction was found to be impaired in adolescent males. We also observed lower levels of GluA1, GLUN2A and GLUN2B subunits in male adolescents following fear acquisition, with an increase in their expression, as well as the activity of Erk-mTOR pathway over subsequent extinction sessions, which was paralleled with improved extinction learning. On the other hand, we detected no changes in plasticity-related proteins after fear acquisition in females, with alterations in GluA1, GluA4 and GLUN2B levels across fear extinction sessions. Additionally, we did not discern any pattern regarding the Erk-mTOR activity in female mice associated with their extinction performance. Overall, our research identifies sex-specific synaptic properties in the hippocampus that underlie developmentally regulated differences in fear extinction learning. We also point out hippocampal NMDA-Erk-mTOR signaling as the driving force behind successful fear extinction in male adolescents, highlighting this pathway as a potential therapeutic target for fear-related disorders in the adolescent population. © 2022 The Authors
T2  - Brain Research Bulletin
T1  - Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice
VL  - 192
SP  - 156
EP  - 167
DO  - 10.1016/j.brainresbull.2022.11.011
ER  - 

@article{
author = "Glavonić, Emilija and Mitić, Miloš and Francija, Ester and Petrović, Zorica and Adžić, Miroslav",
year = "2023",
abstract = "Adolescence is a key phase of development for perturbations in fear extinction, with inability to adequately manage fear a potent factor for developing psychiatric disorders in adulthood. However, while behavioral correlates of adolescent fear regulation are established to a degree, molecular mediators of extinction learning in adolescence remain largely unknown. In this study, we observed fear acquisition and fear extinction (across 4 and 7 days) of adolescent and adult mice of both sexes and investigated how hippocampal levels of different plasticity markers relate to extinction learning. While fear was acquired evenly in males and females of both ages, fear extinction was found to be impaired in adolescent males. We also observed lower levels of GluA1, GLUN2A and GLUN2B subunits in male adolescents following fear acquisition, with an increase in their expression, as well as the activity of Erk-mTOR pathway over subsequent extinction sessions, which was paralleled with improved extinction learning. On the other hand, we detected no changes in plasticity-related proteins after fear acquisition in females, with alterations in GluA1, GluA4 and GLUN2B levels across fear extinction sessions. Additionally, we did not discern any pattern regarding the Erk-mTOR activity in female mice associated with their extinction performance. Overall, our research identifies sex-specific synaptic properties in the hippocampus that underlie developmentally regulated differences in fear extinction learning. We also point out hippocampal NMDA-Erk-mTOR signaling as the driving force behind successful fear extinction in male adolescents, highlighting this pathway as a potential therapeutic target for fear-related disorders in the adolescent population. © 2022 The Authors",
journal = "Brain Research Bulletin",
title = "Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice",
volume = "192",
pages = "156-167",
doi = "10.1016/j.brainresbull.2022.11.011"
}

Glavonić, E., Mitić, M., Francija, E., Petrović, Z.,& Adžić, M.. (2023). Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice. in Brain Research Bulletin, 192, 156-167.
https://doi.org/10.1016/j.brainresbull.2022.11.011

Glavonić E, Mitić M, Francija E, Petrović Z, Adžić M. Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice. in Brain Research Bulletin. 2023;192:156-167.
doi:10.1016/j.brainresbull.2022.11.011 .

Glavonić, Emilija, Mitić, Miloš, Francija, Ester, Petrović, Zorica, Adžić, Miroslav, "Sex-specific role of hippocampal NMDA-Erk-mTOR signaling in fear extinction of adolescent mice" in Brain Research Bulletin, 192 (2023):156-167,
https://doi.org/10.1016/j.brainresbull.2022.11.011 . .

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 . .

TY  - JOUR
AU  - Francija, Ester
AU  - Petrović, Zorica
AU  - Brkić, Željka
AU  - Mitić, Miloš
AU  - Radulović, Jelena
AU  - Adžić, Miroslav
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8450
AB  - Recent reports have demonstrated that lipopolysaccharide (LPS)-induced depressive-like behaviour is mediated via NMDA receptor. In this study, we further investigated the role of GluN2 A subunit of NMDA receptor in synaptic processes in the prefrontal cortex (PFC) and hippocampus of GluN2 A knockout (KO) mice in LPS-induced depressive-like behavior. Our data suggest that LPS-treated mice, lacking GluN2 A subunit, did not exhibit depressive-like behaviour. This was accompanied by unaltered levels of IL-6 and significant changes in neuroplasticity markers and glutamate receptor subunits composition in PFC and hippocampus. In particular, an immune challenge in GluN2 A KO mice resulted in unchanged PSA-NCAM levels and proBDNF increase in both brain structures as well as in increase in BDNF levels in hippocampus. Furthermore, the absence of GluN2 A resulted in increased levels of all NCAM isoforms in PFC upon LPS which was followed with a decrease in GluN1 and GluN2B subunits. The levels of AMPA receptor subunits (GluA1, GluA3, and GluA4) in the hippocampus of GluN2 A mice were unaltered upon the treatment and abundantly present in the PFC of KO mice. These results indicate that the GluN2 A subunit is critical in neuroinflammation-related depression, that its absence abolishes LPS-induced depressive phenotype, sustains PSA-NCAM levels, increases proBDNF signalling in the PFC and hippocampus and potentiates synaptic stabilization through NCAM in the PFC upon an immune challenge. © 2018 Elsevier B.V.
T2  - Behavioural Brain Research
T1  - Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression
VL  - 359
SP  - 550
EP  - 559
DO  - 10.1016/j.bbr.2018.10.011
ER  - 

@article{
author = "Francija, Ester and Petrović, Zorica and Brkić, Željka and Mitić, Miloš and Radulović, Jelena and Adžić, Miroslav",
year = "2019",
abstract = "Recent reports have demonstrated that lipopolysaccharide (LPS)-induced depressive-like behaviour is mediated via NMDA receptor. In this study, we further investigated the role of GluN2 A subunit of NMDA receptor in synaptic processes in the prefrontal cortex (PFC) and hippocampus of GluN2 A knockout (KO) mice in LPS-induced depressive-like behavior. Our data suggest that LPS-treated mice, lacking GluN2 A subunit, did not exhibit depressive-like behaviour. This was accompanied by unaltered levels of IL-6 and significant changes in neuroplasticity markers and glutamate receptor subunits composition in PFC and hippocampus. In particular, an immune challenge in GluN2 A KO mice resulted in unchanged PSA-NCAM levels and proBDNF increase in both brain structures as well as in increase in BDNF levels in hippocampus. Furthermore, the absence of GluN2 A resulted in increased levels of all NCAM isoforms in PFC upon LPS which was followed with a decrease in GluN1 and GluN2B subunits. The levels of AMPA receptor subunits (GluA1, GluA3, and GluA4) in the hippocampus of GluN2 A mice were unaltered upon the treatment and abundantly present in the PFC of KO mice. These results indicate that the GluN2 A subunit is critical in neuroinflammation-related depression, that its absence abolishes LPS-induced depressive phenotype, sustains PSA-NCAM levels, increases proBDNF signalling in the PFC and hippocampus and potentiates synaptic stabilization through NCAM in the PFC upon an immune challenge. © 2018 Elsevier B.V.",
journal = "Behavioural Brain Research",
title = "Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression",
volume = "359",
pages = "550-559",
doi = "10.1016/j.bbr.2018.10.011"
}

Francija, E., Petrović, Z., Brkić, Ž., Mitić, M., Radulović, J.,& Adžić, M.. (2019). Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression. in Behavioural Brain Research, 359, 550-559.
https://doi.org/10.1016/j.bbr.2018.10.011

Francija E, Petrović Z, Brkić Ž, Mitić M, Radulović J, Adžić M. Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression. in Behavioural Brain Research. 2019;359:550-559.
doi:10.1016/j.bbr.2018.10.011 .

Francija, Ester, Petrović, Zorica, Brkić, Željka, Mitić, Miloš, Radulović, Jelena, Adžić, Miroslav, "Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression" in Behavioural Brain Research, 359 (2019):550-559,
https://doi.org/10.1016/j.bbr.2018.10.011 . .

TY  - JOUR
AU  - Adžić, Miroslav
AU  - Glavonić, Emilija
AU  - Nešić, Milica J.
AU  - Milosavljević, Minja
AU  - Mihaljević, Marina
AU  - Petrović, Zorica D.
AU  - Pavlović, Zorana
AU  - Brkić, Željka
AU  - Francija, Ester
AU  - Soldatović, Ivan A.
AU  - Mitić, Miloš
AU  - Radulović, Jelena
AU  - Marić, Nađa P.
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8010
AB  - Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα their interactions and FKBP5 explained 22%–35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα and emphasized its role in fear extinction and neural plasticity. © 2018 Elsevier Inc.
T2  - Progress in Neuro-Psychopharmacology and Biological Psychiatry
T1  - Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states
VL  - 90
SP  - 288
EP  - 299
DO  - 10.1016/j.pnpbp.2018.12.011
ER  - 

@article{
author = "Adžić, Miroslav and Glavonić, Emilija and Nešić, Milica J. and Milosavljević, Minja and Mihaljević, Marina and Petrović, Zorica D. and Pavlović, Zorana and Brkić, Željka and Francija, Ester and Soldatović, Ivan A. and Mitić, Miloš and Radulović, Jelena and Marić, Nađa P.",
year = "2019",
abstract = "Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα their interactions and FKBP5 explained 22%–35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα and emphasized its role in fear extinction and neural plasticity. © 2018 Elsevier Inc.",
journal = "Progress in Neuro-Psychopharmacology and Biological Psychiatry",
title = "Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states",
volume = "90",
pages = "288-299",
doi = "10.1016/j.pnpbp.2018.12.011"
}

Adžić, M., Glavonić, E., Nešić, M. J., Milosavljević, M., Mihaljević, M., Petrović, Z. D., Pavlović, Z., Brkić, Ž., Francija, E., Soldatović, I. A., Mitić, M., Radulović, J.,& Marić, N. P.. (2019). Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states. in Progress in Neuro-Psychopharmacology and Biological Psychiatry, 90, 288-299.
https://doi.org/10.1016/j.pnpbp.2018.12.011

Adžić M, Glavonić E, Nešić MJ, Milosavljević M, Mihaljević M, Petrović ZD, Pavlović Z, Brkić Ž, Francija E, Soldatović IA, Mitić M, Radulović J, Marić NP. Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states. in Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019;90:288-299.
doi:10.1016/j.pnpbp.2018.12.011 .

Adžić, Miroslav, Glavonić, Emilija, Nešić, Milica J., Milosavljević, Minja, Mihaljević, Marina, Petrović, Zorica D., Pavlović, Zorana, Brkić, Željka, Francija, Ester, Soldatović, Ivan A., Mitić, Miloš, Radulović, Jelena, Marić, Nađa P., "Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states" in Progress in Neuro-Psychopharmacology and Biological Psychiatry, 90 (2019):288-299,
https://doi.org/10.1016/j.pnpbp.2018.12.011 . .

TY  - JOUR
AU  - Adžić, Miroslav
AU  - Brkić, Željka
AU  - Mitić, Miloš
AU  - Francija, Ester
AU  - Jovičić, Milica J.
AU  - Radulović, Jelena
AU  - Marić, Nađa P.
PY  - 2018
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1939
AB  - Background: Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation- withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation. Methods: In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies. Results: Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression. Conclusion: The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of antiinflammatory co-treatments, is required.
T2  - Current Neuropharmacology
T1  - Therapeutic Strategies for Treatment of Inflammation-related Depression
VL  - 16
IS  - 2
SP  - 176
EP  - 209
DO  - 10.2174/1570159X15666170828163048
ER  - 

@article{
author = "Adžić, Miroslav and Brkić, Željka and Mitić, Miloš and Francija, Ester and Jovičić, Milica J. and Radulović, Jelena and Marić, Nađa P.",
year = "2018",
abstract = "Background: Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation- withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation. Methods: In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies. Results: Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression. Conclusion: The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of antiinflammatory co-treatments, is required.",
journal = "Current Neuropharmacology",
title = "Therapeutic Strategies for Treatment of Inflammation-related Depression",
volume = "16",
number = "2",
pages = "176-209",
doi = "10.2174/1570159X15666170828163048"
}

Adžić, M., Brkić, Ž., Mitić, M., Francija, E., Jovičić, M. J., Radulović, J.,& Marić, N. P.. (2018). Therapeutic Strategies for Treatment of Inflammation-related Depression. in Current Neuropharmacology, 16(2), 176-209.
https://doi.org/10.2174/1570159X15666170828163048

Adžić M, Brkić Ž, Mitić M, Francija E, Jovičić MJ, Radulović J, Marić NP. Therapeutic Strategies for Treatment of Inflammation-related Depression. in Current Neuropharmacology. 2018;16(2):176-209.
doi:10.2174/1570159X15666170828163048 .

Adžić, Miroslav, Brkić, Željka, Mitić, Miloš, Francija, Ester, Jovičić, Milica J., Radulović, Jelena, Marić, Nađa P., "Therapeutic Strategies for Treatment of Inflammation-related Depression" in Current Neuropharmacology, 16, no. 2 (2018):176-209,
https://doi.org/10.2174/1570159X15666170828163048 . .

TY  - JOUR
AU  - Brkić, Željka
AU  - Francija, Ester
AU  - Petrović, Zorica D.
AU  - Franić, Dušanka
AU  - Lukić, Iva
AU  - Mitić, Miloš
AU  - Adžić, Miroslav
PY  - 2017
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1888
AB  - Inflammation plays a critical role in pathogenesis of depression and can affect the hypothalamic-pituitary-adrenal axis activity. Accordingly, in this study we investigated the role of hippocampal glucocorticoid receptor in mediating the effects of inflammation on behaviour of female and male Wistar rats. We studied the effects of lipopolysaccharide on the levels of glucocorticoid receptors and its co-chaperones FK506 binding protein 52 and FK506 binding protein 51, the levels of glucocorticoid receptor phospho-isoforms, pGR-232 and pGR-246, and glucocorticoid receptor up-stream kinases. In order to assess transcriptional activity of glucocorticoid receptor, we measured mRNA levels of several glucocorticoid receptor-regulated genes. We demonstrated that lipopolysaccharide induced depressive-like behaviour and elevated serum corticosterone in both sexes. However, it affected glucocorticoid receptor signalling in the nucleus of females and males differently-in females it elevated levels of glucocorticoid receptors, pGR-246 and FK506 binding protein 52, while in males it decreased levels of glucocorticoid receptor, both co-chaperons and pGR-246. Alterations in pGR-246 were associated with alterations of c-Jun N-terminal kinases. Altered nuclear levels of total glucocorticoid receptors and pGR-246 were accompanied by sex-specific reduction in brain-derived neurotrophic factor and cyclooxygenase-2 mRNA and sex-unspecific reduction in the expression of p11 and glucocorticoid receptor genes. These alterations may ultimately affect different glucocorticoid receptor-associated processes involved in depressive-like behaviour in males and females.
T2  - Journal of Psychopharmacology
T1  - Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats
VL  - 31
IS  - 9
SP  - 1234
EP  - 1249
DO  - 10.1177/0269881117725914
ER  - 

@article{
author = "Brkić, Željka and Francija, Ester and Petrović, Zorica D. and Franić, Dušanka and Lukić, Iva and Mitić, Miloš and Adžić, Miroslav",
year = "2017",
abstract = "Inflammation plays a critical role in pathogenesis of depression and can affect the hypothalamic-pituitary-adrenal axis activity. Accordingly, in this study we investigated the role of hippocampal glucocorticoid receptor in mediating the effects of inflammation on behaviour of female and male Wistar rats. We studied the effects of lipopolysaccharide on the levels of glucocorticoid receptors and its co-chaperones FK506 binding protein 52 and FK506 binding protein 51, the levels of glucocorticoid receptor phospho-isoforms, pGR-232 and pGR-246, and glucocorticoid receptor up-stream kinases. In order to assess transcriptional activity of glucocorticoid receptor, we measured mRNA levels of several glucocorticoid receptor-regulated genes. We demonstrated that lipopolysaccharide induced depressive-like behaviour and elevated serum corticosterone in both sexes. However, it affected glucocorticoid receptor signalling in the nucleus of females and males differently-in females it elevated levels of glucocorticoid receptors, pGR-246 and FK506 binding protein 52, while in males it decreased levels of glucocorticoid receptor, both co-chaperons and pGR-246. Alterations in pGR-246 were associated with alterations of c-Jun N-terminal kinases. Altered nuclear levels of total glucocorticoid receptors and pGR-246 were accompanied by sex-specific reduction in brain-derived neurotrophic factor and cyclooxygenase-2 mRNA and sex-unspecific reduction in the expression of p11 and glucocorticoid receptor genes. These alterations may ultimately affect different glucocorticoid receptor-associated processes involved in depressive-like behaviour in males and females.",
journal = "Journal of Psychopharmacology",
title = "Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats",
volume = "31",
number = "9",
pages = "1234-1249",
doi = "10.1177/0269881117725914"
}

Brkić, Ž., Francija, E., Petrović, Z. D., Franić, D., Lukić, I., Mitić, M.,& Adžić, M.. (2017). Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats. in Journal of Psychopharmacology, 31(9), 1234-1249.
https://doi.org/10.1177/0269881117725914

Brkić Ž, Francija E, Petrović ZD, Franić D, Lukić I, Mitić M, Adžić M. Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats. in Journal of Psychopharmacology. 2017;31(9):1234-1249.
doi:10.1177/0269881117725914 .

Brkić, Željka, Francija, Ester, Petrović, Zorica D., Franić, Dušanka, Lukić, Iva, Mitić, Miloš, Adžić, Miroslav, "Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats" in Journal of Psychopharmacology, 31, no. 9 (2017):1234-1249,
https://doi.org/10.1177/0269881117725914 . .