Iivanainen, V. | Search bioRxiv

bioRxiv2024

Serotonin system development and adult function are regulated by GDNF

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.

neuroscience↗

bioRxiv2024

Motor learning is regulated by GDNF levels in postnatal cerebellar Purkinje cells

Purkinje cells, the sole output neurons of the cerebellar cortex, are crucial for cerebellum-dependent motor learning. Previously we demonstrated that a ubiquitous 2-3-fold increase of endogenous glial cell line-derived neurotrophic factor (GDNF) improves motor learning. However, GDNF impacts many organ systems and cell types throughout the body leaving the underlying mechanism elusive. Here, we utilize an innovative conditional GDNF Hypermorphic mouse model to show that a 2-fold increase in endogenous GDNF specifically in postnatal Purkinje cells (PCs) is sufficient to enhance motor learning in adult animals. We demonstrate that improved motor learning is associated with increased glutamatergic input to PCs and elevated spontaneous firing rate of these cells, opposite to cerebellar ataxia where reduction in motor function and learning associates with decreased spontaneous activity of PCs. Notably, the GDNF expression levels variation range studied in our mouse models cerebellum falls within the normal range of variation observed in healthy human cerebellums. Our findings uncover a molecular pathway and a specific cell type that regulate motor learning, potentially explaining some individual differences in human motor skill acquisition.

neuroscience↗