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

Abstract

Proper regulation of arousal maintains the balance of rest and activity and enables appropriate responses to stimuli; its disruption is a hallmark of many neurodevelopmental disorders. Although transcriptional mechanisms of arousal control are well defined, the contribution of posttranscriptional processes such as alternative splicing remains unclear. Here, we identify a critical role for the microexon splicing regulator <i>srrm3</i> in maintaining arousal homeostasis in zebrafish. <i>srrm3</i> mutants exhibit persistent hyperarousal characterized by sleep loss, sensory hypersensitivity, and elevated behavioral and neuronal activity. We identify the cyclic adenosine monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling axis as a central driver of mutant hyperarousal. Specifically, pharmacological inhibition of cAMP signaling rescues mutant hyperactivity and associated transcriptional changes whereas wild-type cAMP activation phenocopies the mutant. Down-regulation of immediate early genes and reduced CREB phosphorylation further suggest adaptation to sustained neuronal activation. These findings establish <i>srrm3</i>-dependent microexon splicing as a key molecular layer of arousal regulation linking RNA-processing defects to neuromodulatory imbalance.