Serotonin system development and adult function are regulated by GDNF

Garton, D. R.; Runneberger, I.; Casserly, L.; Schorling, T.; Montano-Rodriguez, A. R.; Iivanainen, V.; Kopra, J. J.; Mätlik, K.; Fagerström-Billai, F.; Damdimopoulos, A.; Piepponen, T. P.; Andressoo, J.-O.

doi:10.1101/2024.12.11.627811

bioRxiv · 10.1101/2024.12.11.627811

Serotonin system development and adult function are regulated by GDNF

Garton, D. R.·Runneberger, I.·Casserly, L.·Schorling, T.·Montano-Rodriguez, A. R.·Iivanainen, V.·Kopra, J. J.·Mätlik, K.·Fagerström-Billai, F.·Damdimopoulos, A.·Piepponen, T. P.·Andressoo, J.-O.

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Abstract

Cognitive functions, neuropsychiatric disorders and behaviors from feeding to mood relate to the serotonin (5-hydroxytryptamine; 5-HT) system. We report that expression of glial cell line-derived neurotrophic factor (GDNF), a known potent stimulator of the brain dopamine system, correlates with serotonergic markers in humans, and increased GDNF defines a subset of psychiatric patients with a characteristic 5-HT-related gene expression pattern. A similar [~]1.5- to 2-fold upregulation of endogenous GDNF expression in mice increases brain 5-HT levels and function, both developmentally and during adulthood, and modulates response to fluoxetine. Notably, increasing GDNF more than approximately 2-fold does not increase 5-HT further and instead produces an inverted U-shaped curve of 5-HT levels, suggesting why the GDNF/5-HT correlation has remained controversial. Collectively, our data indicate that GDNF levels fine-tune 5-HT system development and adult function while excess GDNF exclusively associates with neuropsychiatric illness, making it an important target for future research.

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Garton, D. R., Runneberger, I., Casserly, L., Schorling, T., Montano-Rodriguez, A. R., Iivanainen, V., Kopra, J. J., Mätlik, K., Fagerström-Billai, F., Damdimopoulos, A., Piepponen, T. P., Andressoo, J.-O.. 2024-12-11. Serotonin system development and adult function are regulated by GDNF. https://doi.org/10.1101/2024.12.11.627811

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