Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia.

Autor: Mätlik K; Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. kmatlik01@rockefeller.edu., Garton DR; Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland., Montaño-Rodríguez AR; Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland., Olfat S; Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland.; Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14183, Huddinge, Sweden., Eren F; Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden., Casserly L; Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland., Damdimopoulos A; Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden., Panhelainen A; Institute of Biotechnology, University of Helsinki, 00014, Helsinki, Finland., Porokuokka LL; Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland., Kopra JJ; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Helsinki, Finland., Turconi G; Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland., Schweizer N; Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14183, Huddinge, Sweden., Bereczki E; Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14183, Huddinge, Sweden., Piehl F; Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, 17177, Stockholm, Sweden., Engberg G; Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden., Cervenka S; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, 17177, Stockholm, Sweden.; Department of Medical Sciences, Psychiatry, Uppsala University, 75185, Uppsala, Sweden., Piepponen TP; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Helsinki, Finland., Zhang FP; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, 20520, Turku, Finland.; GM-Unit, Laboratory Animal Center, Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland., Sipilä P; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, 20520, Turku, Finland., Jakobsson J; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84, Lund, Sweden., Sellgren CM; Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden.; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, 17177, Stockholm, Sweden., Erhardt S; Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden., Andressoo JO; Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. jaan-olle.andressoo@helsinki.fi.; Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14183, Huddinge, Sweden. jaan-olle.andressoo@helsinki.fi.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Aug; Vol. 27 (8), pp. 3247-3261. Date of Electronic Publication: 2022 May 26.
DOI: 10.1038/s41380-022-01554-2
Abstrakt: Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2-3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A 2A R), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A 2A R with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A 2A R crosstalk may regulate dopamine function in a therapeutically targetable manner.
(© 2022. The Author(s).)
Databáze: MEDLINE
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