Neural microexons modulate arousal states via cAMP signalling in zebrafish

Arousal states, often dysregulated in neurodevelopmental disorders, shape how organisms perceive and respond to their environment. Here, we show thatsrrm3, a master regulator of neural microexons, is essential for normal arousal in zebrafish larvae.srrm3mutants 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 reversessrrm3-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,srrm3mutants 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.