The involvement of the GPR39-Zn(2+)-sensing receptor in the pathophysiology of depression. Studies in rodent models and suicide victims

Młyniec, Katarzyna; Doboszewska, Urszula; Szewczyk, Bernadeta; Sowa-Kućma, Magdalena; Misztak, Paulina; Piekoszewski, Wojciech; Trela, Franciszek; Ostachowicz, Beata; Nowak, Gabriel

doi:10.1016/j.neuropharm.2013.12.001

Cited by 61 publications

(55 citation statements)

References 52 publications

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“…Of note, zinc-deficient diet for six weeks is associated with a significant reduction in GPR39 receptor and brain-derived neurotrophic factor (BDNF) protein expression in the frontal cortex of mice as well as a depressive-like behavior . Zinc-deficient diet for six weeks also decreased expression of CREB and BDNF in the hippocampus (Mlyniec et al, 2014). GPR39 expression was decreased in the hippocampus and frontal cortex of zinc deficient mice and rats as well as in the hippocampus and cerebral cortex of suicide victims (Mlyniec et al, 2014).…”

Section: Introductionmentioning

confidence: 95%

“…Zinc-deficient diet for six weeks also decreased expression of CREB and BDNF in the hippocampus (Mlyniec et al, 2014). GPR39 expression was decreased in the hippocampus and frontal cortex of zinc deficient mice and rats as well as in the hippocampus and cerebral cortex of suicide victims (Mlyniec et al, 2014). Zinc deficient diet for four or six weeks also decreased p-CREB and BDNF levels in the hippocampus (Doboszewska et al, 2015).…”

Section: Introductionmentioning

confidence: 98%

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Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

Manosso

Moretti

Ribeiro

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Considering that intracellular signaling pathways that modulate brain BDNF are implicated in antidepressant responses, this study investigated whether signaling pathway inhibitors upstream to BDNF might influence the antidepressant-like effect of zinc, a metal that has been shown to display antidepressant properties. To this end, the influence of i.c.v. administration of H-89 (1μg/site, PKA inhibitor), KN-62 (1μg/site, CAMKII inhibitor), chelerythrine (1μg/site, PKC inhibitor), PD98059 (5μg/site, MEK1/2 inhibitor), U0126 (5μg/site, MEK1/2 inhibitor), LY294002 (10nmol/site, PI3K inhibitor) on the reduction of immobility time in the tail suspension test (TST) elicited by ZnCl2 (10mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl2 (1mg/kg, p.o.) and AR-A014418 (0.001μg/site, GSK-3β inhibitor) was evaluated. The occurrence of changes in CREB phosphorylation and BDNF immunocontent in the hippocampus and prefrontal cortex of mice following ZnCl2 treatment was also investigated. The anti-immobility effect of ZnCl2 in the TST was prevented by treatment with PKA, PKC, CAMKII, MEK1/2 or PI3K inhibitors. Furthermore, ZnCl2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl2 treatment caused no alteration in CREB phosphorylation and BDNF immunocontent. The results extend literature data regarding the mechanisms underlying the antidepressant-like action of zinc by indicating that its antidepressant-like effect may be dependent on the activation of PKA, CAMKII, PKC, ERK, and PI3K/GSK-3β pathways. However, zinc is not able to acutely increase BDNF in the hippocampus and prefrontal cortex.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

Manosso

Moretti

Ribeiro

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…Concerning cell survival, it has been reported that increased apoptotic cell death in hippocampal regions (including CA1, CA3, and dentate gyrus) and decreased phosphorylation of hippocampal TrkB and ERK were observed in lactating zinc deficient (0.85 ppm) mice (135). Importantly, a zinc deficient diet (0.2 and 1 ppm) for 3 and 6 weeks caused depressive and anxiety-like behaviors in addition to anhedonia (136–138), while these depressive-like behaviors were reversed after chronic treatment with typical antidepressants (such as fluoxetine, imipramine, and reboxetine) (136, 138). In addition, such zinc deficiency in the diet induced downregulation of GPR39, BDNF, and its receptor TrkB in both hippocampal and cortical regions when compared with adequate zinc (33.5 ppm) (138).…”

Section: Action Of Zinc In Depressionmentioning

confidence: 99%

“…Importantly, a zinc deficient diet (0.2 and 1 ppm) for 3 and 6 weeks caused depressive and anxiety-like behaviors in addition to anhedonia (136–138), while these depressive-like behaviors were reversed after chronic treatment with typical antidepressants (such as fluoxetine, imipramine, and reboxetine) (136, 138). In addition, such zinc deficiency in the diet induced downregulation of GPR39, BDNF, and its receptor TrkB in both hippocampal and cortical regions when compared with adequate zinc (33.5 ppm) (138). All these studies suggest that the possibility of zinc homeostasis is associated with mood status and BDNF-related neuronal function.…”

Section: Action Of Zinc In Depressionmentioning

confidence: 99%

The Role of Brain-Derived Neurotrophic Factor in Comorbid Depression: Possible Linkage with Steroid Hormones, Cytokines, and Nutrition

et al. 2014

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Increasing evidence demonstrates a connection between growth factor function (including brain-derived neurotrophic factor, BDNF), glucocorticoid levels (one of the steroid hormones), and the pathophysiology of depressive disorders. Because both BDNF and glucocorticoids regulate synaptic function in the central nervous system, their functional interaction is of major concern. Interestingly, alterations in levels of estrogen, another steroid hormone, may play a role in depressive-like behavior in postpartum females with fluctuations of BDNF-related molecules in the brain. BDNF and cytokines, which are protein regulators of inflammation, stimulate multiple intracellular signaling cascades involved in neuropsychiatric illness. Pro-inflammatory cytokines may increase vulnerability to depressive symptoms, such as the increased risk observed in patients with cancer and/or autoimmune diseases. In this review, we discuss the possible relationship between inflammation and depression, in addition to the cross-talk among cytokines, BDNF, and steroids. Further, since nutritional status has been shown to affect critical pathways involved in depression through both BDNF function and the monoamine system, we also review current evidence surrounding diet and supplementation (e.g., flavonoids) on BDNF-mediated brain functions.

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“…Our previous studies performed in postmortem tissue of suicide victims showed no siginificant difference in total Zn levels in the prefrontal cortex (PFC) and hippocampus as compared to control subjects (Nowak et al, 2003; Sowa-Kucma et al, 2013). However, another study revealed alterations in the Zn interaction with N-methyl-D-aspartate receptors (NMDA) (Nowak et al, 2003; Sowa-Kucma et al, 2013) and a decreased in levels of GPR39-Zn(2+)-sensing receptor in the brain of suicide victims (Mlyniec et al, 2014). Thus, there is indirect evidence for a disruption in Zn homeostasis in the pathophysiology of suicide.…”

Section: Introductionmentioning

confidence: 99%

Zinc transporters protein level in postmortem brain of depressed subjects and suicide victims

Rafało-Ulińska

Piotrowska

Kryczyk

et al. 2016

Journal of Psychiatric Research

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Background Major depressive disorder (MDD) is a serious psychiatric illness, associated with an increasing rate of suicide. The pathogenesis of depression may be associated with the disruption of zinc (Zn) homeostasis. In the brain, several proteins that regulate Zn homeostasis are present, including Zn transporters (ZnTs) which remove Zn from the cytosol. The present study was designed to investigate whether depression and suicide are associated with alterations in the expression of the ZnTs protein. Methods Protein levels of ZnT1, ZnT3, ZnT4, ZnT5 and ZnT6 were measured in postmortem brain tissue from two different cohorts. Cohort A contained 10 subjects diagnosed with MDD (7 were suicide victims) and 10 psychiatrically-normal control subjects and cohort B contained 11 non-diagnosed suicide victims and 8 sudden-death control subjects. Moreover, in cohort A we measured protein level of NMDA (GluN2A subunit), AMPA (GluA1 subunit) and 5-HT1A receptors and PSD-95. Proteins were measured in the prefrontal cortex (PFC) using Western blotting. In addition, Zn concentration was measured using a voltammetric method. Results There was a significant increase in protein levels of ZnT1, ZnT4, ZnT5 in the PFC in MDD, relative to control subjects, while ZnT3 protein level was decreased in MDD. There was no significant difference in the Zn concentration in the PFC between control and MDD subjects. Similarly, in the PFC of suicide victims (non-diagnosed), an increase in protein levels of ZnT1, ZnT4, ZnT5 and ZnT6 was observed. Conversely, protein levels of ZnT3 were decreased in both suicide victims and subjects with MDD, in comparison with control subjects. There was also a significant decrease in the protein level of GluA1, GluN2A, PSD-95 and 5-HT1A in MDD. Conclusions Our studies suggest that alterations in Zn transport proteins are associated with the pathophysiology of MDD and suicide.

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The involvement of the GPR39-Zn(2+)-sensing receptor in the pathophysiology of depression. Studies in rodent models and suicide victims

Cited by 61 publications

References 52 publications

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

The Role of Brain-Derived Neurotrophic Factor in Comorbid Depression: Possible Linkage with Steroid Hormones, Cytokines, and Nutrition

Zinc transporters protein level in postmortem brain of depressed subjects and suicide victims

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