Anna Rafalo-Ulinska1, Joanna Piotrowska2, Agata Kryczyk2, Włodzimierz Opoka2, Magdalena Sowa-Kucma3, Paulina Misztak4, Grazyna Rajkowska5, Craig A Stockmeier6, Wojciech Datka7, Gabriel Nowak4, Bernadeta Szewczyk8. 1. Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland; Institute of Zoology, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland. 2. Department of Inorganic and Analytical Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland. 3. Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland. 4. Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland; Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland. 5. Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. 6. Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA; Department of Psychiatry, Case Western Reserve University, 10524 Euclid Avenue, Cleveland, OH 44106, USA. 7. Department of Affective Disorders, Jagiellonian University Medical College, Kopernika 21a, 31-501 Kraków, Poland. 8. Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland. Electronic address: szewczyk@if-pan.krakow.pl.
Abstract
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.
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.
Authors: J A Cobb; K O'Neill; J Milner; G J Mahajan; T J Lawrence; W L May; J Miguel-Hidalgo; G Rajkowska; C A Stockmeier Journal: Neuroscience Date: 2015-12-30 Impact factor: 3.590
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