Neuronal microexons modulate arousal via the cAMP-PKA-CREB pathway in zebrafish

While transcriptional mechanisms of arousal control are well-defined, the contribution of post-transcriptional processes such as alternative splicing remains unclear. Here, we identify a critical role for the microexon splicing regulator srrm3 in maintaining arousal homeostasis in zebrafish. srrm3 mutants exhibit persistent hyperarousal characterized by sleep loss, sensory hypersensitivity, and elevated behavioural and neuronal activity.

We identify the cAMP-PKA-CREB signaling axis as a central driver of mutant hyperarousal. Specifically, pharmacological inhibition of cAMP signalling rescues mutant hyperactivity and associated transcriptional changes while wild-type cAMP activation phenocopies the mutant. Downregulation of immediate early genes and a reduced CREB phosphorylation further suggest adaptation to sustained neuronal activation.