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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Arousal regulation is crucial for normal brain function and its disruption is linked to neurodevelopmental disorders.
• While transcriptional control of arousal is understood, the role of posttranscriptional processes like alternative splicing is less clear.

Purpose of the Study:

• To investigate the role of the microexon splicing regulator srrm3 in maintaining arousal homeostasis.
• To elucidate the molecular mechanisms underlying srrm3-dependent arousal regulation.

Main Methods:

• Utilized zebrafish (Danio rerio) as a model organism.
• Generated and analyzed srrm3 mutants to observe arousal phenotypes.
• Investigated the involvement of the cyclic adenosine monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling pathway.

Main Results:

• srrm3 mutants displayed persistent hyperarousal, including sleep loss, sensory hypersensitivity, and increased neuronal activity.
• The cAMP-PKA-CREB signaling axis was identified as a key driver of hyperarousal in mutants.
• Pharmacological inhibition of cAMP signaling rescued mutant phenotypes, while cAMP activation in wild-type fish mimicked the mutant hyperarousal.

Conclusions:

• srrm3-dependent microexon splicing is a critical component of arousal regulation.
• RNA-processing defects can lead to neuromodulatory imbalance and hyperarousal phenotypes.
• This study links microexon splicing to the cAMP signaling pathway in the context of arousal homeostasis.