Neural microexons modulate arousal states via cAMP signalling in zebrafish

Mackensen, T.; Iniguez, L. P.; Mullen, T. S.; Rodriguez-Marin, C.; Kroll, F.; Zuccarini, G.; Fernandez-Albert, J.; Sancho-Vila, L.; Permanyer, J.; Bianco, I. H.; Orger, M. B.; Rihel, J.; Irimia, M.

doi:10.1101/2025.04.24.650407

bioRxiv · 10.1101/2025.04.24.650407

Neural microexons modulate arousal states via cAMP signalling in zebrafish

Mackensen, T.·Iniguez, L. P.·Mullen, T. S.·Rodriguez-Marin, C.·Kroll, F.·Zuccarini, G.·Fernandez-Albert, J.·Sancho-Vila, L.·Permanyer, J.·Bianco, I. H.·Orger, M. B.·Rihel, J.·Irimia, M.

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Abstract

Arousal states, often dysregulated in neurodevelopmental disorders, shape how organisms perceive and respond to their environment. Here, we show that srrm3, a master regulator of neural microexons, is essential for normal arousal in zebrafish larvae. srrm3 mutants exhibit persistent hyperarousal, including sleep loss, sensory hypersensitivity, anxiety-like behaviour, and heightened neural and behavioural activity. Elevated cAMP signalling likely drives this hyperarousal, as pharmacologically reducing cAMP rescues mutant behaviour, while increasing cAMP in wild-type larvae phenocopies the mutant hyperaroused state. Pharmacological cAMP modulation also mimics and reverses srrm3-dependent transcriptional changes. These include immediate early gene downregulation, which, together with altered activity-dependent transcription factor motif occupancy, suggest adaptation to sustained neuronal hyperactivity. Additionally, srrm3 mutants show upregulation of microexon- containing genes, likely compensating for microexon loss. Together, these findings reveal a role for neural microexons in shaping arousal via cAMP signalling, providing insight into how splicing defects may underlie sensory and sleep disturbances.

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Mackensen, T., Iniguez, L. P., Mullen, T. S., Rodriguez-Marin, C., Kroll, F., Zuccarini, G., Fernandez-Albert, J., Sancho-Vila, L., Permanyer, J., Bianco, I. H., Orger, M. B., Rihel, J., Irimia, M.. 2025-04-26. Neural microexons modulate arousal states via cAMP signalling in zebrafish. https://doi.org/10.1101/2025.04.24.650407

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