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

• Published in: Molecular psychiatry Vol. 27; no. 8; pp. 3247 - 3261
• Main Authors: Mätlik, Kärt, Garton, Daniel R., Montaño-Rodríguez, Ana R., Olfat, Soophie, Eren, Feride, Casserly, Laoise, Damdimopoulos, Anastasios, Panhelainen, Anne, Porokuokka, L. Lauriina, Kopra, Jaakko J., Turconi, Giorgio, Schweizer, Nadine, Bereczki, Erika, Piehl, Fredrik, Engberg, Göran, Cervenka, Simon, Piepponen, T. Petteri, Zhang, Fu-Ping, Sipilä, Petra, Jakobsson, Johan, Sellgren, Carl M., Erhardt, Sophie, Andressoo, Jaan-Olle
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2022; Nature Publishing Group
• Subjects: 13/1; 13/51; 38/71; 38/91; 631/1647; 631/378; 64/60; 692/699/476/1799; Animals; Basic Medicine; Behavioral Sciences; Biological Psychology; Cerebrospinal fluid; Corpus Striatum - metabolism; Dopamine; Dopamine - metabolism; Dopamine receptors; G protein-coupled receptors; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Medicinska och farmaceutiska grundvetenskaper; Mental disorders; Mice; Neostriatum; Neurosciences; Neurovetenskaper; Patients; Pharmacotherapy; Prefrontal cortex; Psychiatry; Psychosis; Schizophrenia; Schizophrenia - metabolism; Signal Transduction
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-022-01554-2

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.