Changes in the presence of small pieces of neural genes called microexons cause hyperarousal in zebrafish. This is the main conclusion of an international study led by Universitat Pompeu Fabra (UPF) and the Center for Genome Regulation (CRG). Abnormal patterns of the presence of neural microexons cause a hyperarousal state characterized by increased neural activity and insomnia. This is commonly associated with stress, but also with neurodevelopmental disorders. Arousal control is highly conserved in evolution. Therefore, this finding may help understand the mechanisms underlying some human neurodevelopmental disorders, such as autism and schizophrenia, symptoms associated with microexon mutations.
In order for animals to survive, they must be ready to respond to external and internal stimuli. This central nervous system activation, or arousal, is highly conserved throughout the animal kingdom. Appropriate regulation of arousal allows neural and therefore behavioral responses to maintain a balance between drowsiness and decreased reactivity, insomnia and sensory sensitivities. Two conditions associated with stress and neurodevelopmental disorders.
To properly regulate arousal during development and adulthood, organisms require a wide range of diverse proteins, which is achieved through alternative splicing. This is a process that can generate two functionally distinct proteins with similar but not identical amino acid sequences, depending on the presence or absence of one or more microexons.
Research published in scientific progress In zebrafish, we show that changes due to the presence of neuronal microexons induce a state of hyperarousal. Abnormal fish larvae have altered swimming patterns and reduced sleep. “They sleep less often, sleep for less time, and take longer to fall asleep,” explains Tahnee Mackensen, lead author of the study. Who adds: “It’s interesting to see how analyzing the movements of these transparent larvae can help us remember the fish’s internal state.”
In addition to changes in behavior, the researchers found that the splicing errors alter cAMP levels, a signal produced within cells that regulates neuron activity, making cells more or less excitable. “The abnormal fish is permanently overexcited,” Mackensen revealed. They increase forebrain activity and elevate cAMP signaling, causing daytime hyperactivity. However, this hyperactivity can be normalized by pharmacologically manipulating cAMP.
The study found that lowering cAMP with chemical inhibitors reduced activity in mutant fish to normal levels, while using drugs to maintain high cAMP levels in normal fish mimicked highly excitable behavior by inducing its synthesis or reducing its degradation, confirming that cAMP is key to promoting arousal behavior. In the words of scientists, “in neurons, cAMP acts as a thermostat for their activity.”
Zebrafish research from a human perspective
A series of behavioral and neural changes observed in the abnormal zebrafish had also been reported in flies in a previous study by the same group. “We know that changes in these microexons cause sleep deprivation in fish and flies,” explains study leader Manuel Irimia. He added: “This mechanism is likely conserved in mammals, including humans, but perhaps not in exactly the same way.”
In humans, sleep disturbances and sensory hypersensitivity frequently occur in neurological diseases such as autism and schizophrenia in which alterations in microexon regulation have been reported.
Although not the cause of the disease, we know that changes in protein production may contribute to the symptoms of this disease, and in this sense, it is reasonable to study whether treatments that restore alertness in fish also modify or reduce symptoms in other species. ”
Manuel Irimia, leader of the UPF and CRG Developmental and Evolutionary Transcriptomics Laboratory
This cAMP-regulated arousal pathway is also involved in anxiety and depression. That’s why Mackensen believes it’s worth continuing the investigation because “this could be just the tip of the iceberg.”
sauce:
Pompeu Fabra University – Barcelona
Reference magazines:
Mackensen, T. Others. (2026) Neuronal microexons regulate wakefulness via the cAMP-PKA-CREB pathway in zebrafish. scientific progress. DOI: 10.1126/sciadv.ady8291. https://www.science.org/doi/10.1126/sciadv.ady8291
