PMID- 35618883 OWN - NLM STAT- MEDLINE DCOM- 20221201 LR - 20230412 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 27 IP - 8 DP - 2022 Aug TI - Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia. PG - 3247-3261 LID - 10.1038/s41380-022-01554-2 [doi] AB - 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. CI - (c) 2022. The Author(s). FAU - Matlik, Kart AU - Matlik K AUID- ORCID: 0000-0003-1777-5614 AD - Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. kmatlik01@rockefeller.edu. FAU - Garton, Daniel R AU - Garton DR AD - Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. FAU - Montano-Rodriguez, Ana R AU - Montano-Rodriguez AR AD - Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. FAU - Olfat, Soophie AU - Olfat S AD - Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. AD - Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14183, Huddinge, Sweden. FAU - Eren, Feride AU - Eren F AUID- ORCID: 0000-0001-6068-5329 AD - Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden. FAU - Casserly, Laoise AU - Casserly L AD - Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. FAU - Damdimopoulos, Anastasios AU - Damdimopoulos A AD - Department of Biosciences and Nutrition, Karolinska Institutet, 14183, Huddinge, Sweden. FAU - Panhelainen, Anne AU - Panhelainen A AD - Institute of Biotechnology, University of Helsinki, 00014, Helsinki, Finland. FAU - Porokuokka, L Lauriina AU - Porokuokka LL AD - Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. FAU - Kopra, Jaakko J AU - Kopra JJ AD - Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Helsinki, Finland. FAU - Turconi, Giorgio AU - Turconi G AD - Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. FAU - Schweizer, Nadine AU - Schweizer N AD - Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14183, Huddinge, Sweden. FAU - Bereczki, Erika AU - Bereczki E AD - Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14183, Huddinge, Sweden. FAU - Piehl, Fredrik AU - Piehl F AUID- ORCID: 0000-0001-8329-5219 AD - Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, 17177, Stockholm, Sweden. FAU - Engberg, Goran AU - Engberg G AUID- ORCID: 0000-0003-1659-5232 AD - Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden. FAU - Cervenka, Simon AU - Cervenka S AUID- ORCID: 0000-0001-8103-6977 AD - Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, 17177, Stockholm, Sweden. AD - Department of Medical Sciences, Psychiatry, Uppsala University, 75185, Uppsala, Sweden. FAU - Piepponen, T Petteri AU - Piepponen TP AUID- ORCID: 0000-0002-2318-1612 AD - Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014, Helsinki, Finland. FAU - Zhang, Fu-Ping AU - Zhang FP AD - Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, 20520, Turku, Finland. AD - GM-Unit, Laboratory Animal Center, Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. FAU - Sipila, Petra AU - Sipila P AD - Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, 20520, Turku, Finland. FAU - Jakobsson, Johan AU - Jakobsson J AUID- ORCID: 0000-0003-0669-7673 AD - 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. FAU - Sellgren, Carl M AU - Sellgren CM AD - Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden. AD - Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, 17177, Stockholm, Sweden. FAU - Erhardt, Sophie AU - Erhardt S AUID- ORCID: 0000-0001-7359-5250 AD - Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden. FAU - Andressoo, Jaan-Olle AU - Andressoo JO AUID- ORCID: 0000-0002-0271-3157 AD - Department of Pharmacology, Faculty of Medicine, Neuroscience Center & Helsinki Institute of Life Science, University of Helsinki, 00290, Helsinki, Finland. jaan-olle.andressoo@helsinki.fi. AD - Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, 14183, Huddinge, Sweden. jaan-olle.andressoo@helsinki.fi. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220526 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - VTD58H1Z2X (Dopamine) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) SB - IM MH - Animals MH - Mice MH - *Dopamine/metabolism MH - Glial Cell Line-Derived Neurotrophic Factor/metabolism/pharmacology MH - *Schizophrenia/metabolism MH - Corpus Striatum/metabolism MH - Signal Transduction PMC - PMC9708553 COIS- CMS is a scientific advisor to Outermost Therapeutics Inc. The rest of the authors declare that they have no competing interests. EDAT- 2022/05/27 06:00 MHDA- 2022/12/02 06:00 PMCR- 2022/05/26 CRDT- 2022/05/26 23:28 PHST- 2021/06/14 00:00 [received] PHST- 2022/03/25 00:00 [accepted] PHST- 2022/03/24 00:00 [revised] PHST- 2022/05/27 06:00 [pubmed] PHST- 2022/12/02 06:00 [medline] PHST- 2022/05/26 23:28 [entrez] PHST- 2022/05/26 00:00 [pmc-release] AID - 10.1038/s41380-022-01554-2 [pii] AID - 1554 [pii] AID - 10.1038/s41380-022-01554-2 [doi] PST - ppublish SO - Mol Psychiatry. 2022 Aug;27(8):3247-3261. doi: 10.1038/s41380-022-01554-2. Epub 2022 May 26.