title: GPR39 (zinc receptor) knockout mice exhibit depression-like behavior and CREB/BDNF down-regulation in the hippocampus.
abstract: BACKGROUND
  Zinc may act as a neurotransmitter in the central nervous system by activation of the GPR39 metabotropic receptors.
  
  
  METHODS
  In the present study, we investigated whether GPR39 knockout would cause depressive-like and/or anxiety-like behavior, as measured by the forced swim test, tail suspension test, and light/dark test. We also investigated whether lack of GPR39 would change levels of cAMP response element-binding protein (CREB),brain-derived neurotrophic factor (BDNF) and tropomyosin related kinase B (TrkB) protein in the hippocampus and frontal cortex of GPR39 knockout mice subjected to the forced swim test, as measured by Western-blot analysis.
  
  
  RESULTS
  In this study, GPR39 knockout mice showed an increased immobility time in both the forced swim test and tail suspension test, indicating depressive-like behavior and displayed anxiety-like phenotype. GPR39 knockout mice had lower CREB and BDNF levels in the hippocampus, but not in the frontal cortex, which indicates region specificity for the impaired CREB/BDNF pathway (which is important in antidepressant response) in the absence of GPR39. There were no changes in TrkB protein in either structure. In the present study, we also investigated activity in the hypothalamus-pituitary-adrenal axis under both zinc- and GPR39-deficient conditions. Zinc-deficient mice had higher serum corticosterone levels and lower glucocorticoid receptor levels in the hippocampus and frontal cortex.
  
  
  CONCLUSIONS
  There were no changes in the GPR39 knockout mice in comparison with the wild-type control mice, which does not support a role of GPR39 in hypothalamus-pituitary-adrenal axis regulation. The results of this study indicate the involvement of the GPR39 Zn(2+)-sensing receptor in the pathophysiology of depression with component of anxiety.
authors.affiliation: Department of Biochemical Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Dr. K. Młyniec, Prof. B. Budziszewska); Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland (Profs. B. Budziszewska, G. Nowak); Department of Neuroscience and Pharmacology University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark (Prof. B. Holst); Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Kraków, Poland (Dr. B. Ostachowicz); Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Prof. G. Nowak). katarzyna.mlyniec@uj.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Młyniec
authors.affiliation: Department of Biochemical Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Dr. K. Młyniec, Prof. B. Budziszewska); Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland (Profs. B. Budziszewska, G. Nowak); Department of Neuroscience and Pharmacology University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark (Prof. B. Holst); Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Kraków, Poland (Dr. B. Ostachowicz); Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Prof. G. Nowak).
authors.forename: Bogusława
authors.initials: B
authors.lastname: Budziszewska
authors.affiliation: Department of Biochemical Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Dr. K. Młyniec, Prof. B. Budziszewska); Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland (Profs. B. Budziszewska, G. Nowak); Department of Neuroscience and Pharmacology University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark (Prof. B. Holst); Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Kraków, Poland (Dr. B. Ostachowicz); Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Prof. G. Nowak).
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.affiliation: Department of Biochemical Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Dr. K. Młyniec, Prof. B. Budziszewska); Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland (Profs. B. Budziszewska, G. Nowak); Department of Neuroscience and Pharmacology University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark (Prof. B. Holst); Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Kraków, Poland (Dr. B. Ostachowicz); Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Prof. G. Nowak).
authors.forename: Beata
authors.initials: B
authors.lastname: Ostachowicz
authors.affiliation: Department of Biochemical Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Dr. K. Młyniec, Prof. B. Budziszewska); Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland (Profs. B. Budziszewska, G. Nowak); Department of Neuroscience and Pharmacology University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark (Prof. B. Holst); Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Kraków, Poland (Dr. B. Ostachowicz); Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland (Prof. G. Nowak).
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003623:Dark Adaptation / Q000235:genetics; D003863:Depression / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000378:metabolism*; D046353:Immobility Response, Tonic / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D020813:Receptor, trkB / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D013550:Swimming / Q000523:psychology; D013997:Time Factors; D015032:Zinc / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C512928:GPR39 protein, mouse; D043562:Receptors, G-Protein-Coupled; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D020813:Receptor, trkB; D015032:Zinc; D003345:Corticosterone
keywords: CREB; GPR39; HPA axis; depression; zinc receptor