The altered presence of tiny fragments of neuronal genes, called microexons, causes hyperarousal in zebrafish, according to a study led by Pompeu Fabra University and the Centre for Genomic Regulation released on June 19. The research concludes that an abnormal pattern of neural microexon presence leads to a hyperarousal state characterized by heightened neural activity and insomnia, conditions commonly associated with stress as well as neurodevelopmental disorders.
Arousal regulation is described as highly conserved throughout evolution. The findings could help researchers understand mechanisms underlying certain human neurodevelopmental disorders such as autism and schizophrenia, which are also associated with microexon mutations. Proper arousal regulation ensures that behavioral responses balance between drowsiness or reduced responsiveness and states like insomnia or sensory hypersensitivity.
During development and adulthood, organisms require diverse proteins achieved through alternative splicing—a process producing functionally distinct proteins based on the inclusion or exclusion of microexons. The study published in Science Advances shows that zebrafish larvae with altered neural microexons exhibit abnormal swim patterns and reduced sleep. "They sleep less frequently, for shorter durations, and take longer to fall asleep," said Tahnee Mackensen, first author of the study. Mackensen added, "It is fascinating to see how, by analysing the movement of this transparent larvae, you can recall fish internal states."
Researchers found that mis-splicing alters cAMP levels—a signal within cells regulating neuronal activity—making neurons more excitable. "Abnormal fish are permanently overexcited," Mackensen said. These fish display increased forebrain activity and elevated cAMP signaling responsible for daytime hyperactivity; however, this can be normalized pharmacologically by manipulating cAMP levels.
The study reports that reducing cAMP with a chemical inhibitor lowers mutated fish activity to normal levels while maintaining high cAMP in normal fish induces highly aroused behavior. This confirms cAMP's key role in driving arousal behavior: "in neurons, cAMP acts as a thermostat for its activity," according to the scientists.
Manuel Irimia led the research team: "We do know that the alteration of these microexons causes sleep deprivation in fish and flies," he said. Irimia continued, "this mechanism is likely to be conserved in mammals, including humans, but maybe not in exactly the very same way." Sleep disturbances and sensory hypersensitivity are frequent symptoms in neurological disorders like autism and schizophrenia—both reported to involve altered microexon regulation—and this pathway may also play a role in anxiety and depression.
