Authors
Tahnee Mackensen, Luis Pedro Iñiguez, Thomas Soares Mullen, Cristina Rodriguez-Marin, François Kroll, Giulia Zuccarini, Jordi Fernandez-Albert, Laia Sancho-Vila, Jon Permanyer, Isaac H Bianco, Michael Orger, Jason Rihel, Manuel Irimia
Published in
Science advances. Volume 12. Issue 25. Pages eady8291. Jun 19, 2026. Epub Jun 19, 2026.
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 srrm3 in maintaining arousal homeostasis in zebrafish. srrm3 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 srrm3-dependent microexon splicing as a key molecular layer of arousal regulation linking RNA-processing defects to neuromodulatory imbalance.
PMID:
42319930
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.
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