The altered presence of tiny fragments of neuronal genes, called microexons, causes hyperexcitability in zebrafish. This is the main conclusion of an international study led by Pompeu Fabra University (UPF) and the Center for Genomic Regulation (CRG). An abnormal pattern of presence of neural microexons leads to a state of hyperarousal characterized by increased neural activity and insomnia, usually associated with stress but also with neurodevelopmental disorders. Arousal regulation is highly conserved in evolution. Therefore, this finding could help to understand the mechanism behind some human neurodevelopmental disorders, such as autism and schizophrenia, conditions associated with microexon mutations.
To survive, animals must be ready to react to external and internal stimuli. This activation of the central nervous system, arousal, is largely conserved throughout the animal kingdom. Proper regulation of arousal ensures that neural and thus behavioral responses maintain a balance between sleepiness or reduced responsiveness and insomnia and sensory hypersensitivity. Two conditions related to stress and neurodevelopmental disorders.
To properly regulate stimulation during development and adulthood, organisms require a wide range of different proteins that are achieved through alternative splicing. This is a process that can produce two functionally distinct proteins with a similar but not identical amino acid sequence in response to the presence or absence of one or more microexons.
The study published in Advances in Science shows that, in zebrafish, a change in the presence of neural microexons leads to a state of hyperexcitability. Abnormal fish larvae have an altered swimming pattern and reduced sleep. “They sleep less often, for less time, and take longer to fall asleep,” explains Tahnee Mackensen, first author of the study. He adds, “It’s fascinating to see how, by analyzing the movement of this transparent larva, you can recall the internal states of fish.”
In addition to behavioral changes, the researchers found that mis-splicing alters cAMP levels—a signal produced inside cells that regulates neuronal activity—making them more or less excitable. “Abnormal fish are permanently overstimulated,” explains Mackensen. They have increased forebrain activity and increased cAMP signaling, responsible for daytime hyperactivity. However, this hyperactivity can be normalized by pharmacological manipulation of cAMP.
According to the study, reducing cAMP with a chemical inhibitor reduced the mutant fish’s activity to a normal level, while maintaining high levels of cAMP in normal fish using drugs—either by inducing its synthesis or reducing its degradation—mimics intense stimulation, confirming that cAMP is key to the stimulation. Or in the scientist’s words, “in neurons, cAMP acts as a thermostat for its activity.”
Zebra study with a human angle
The constellation of behavioral and neuronal changes observed in abnormal zebrafish was also reported in flies in a previous study by the same group. “We know that altering these microexons causes sleep deprivation in fish and flies,” explains Manuel Irimia, who led the research. He adds, “this mechanism is likely to be conserved in mammals, including humans, but perhaps not in exactly the same way.”
In humans, sleep disturbances and sensory hypersensitivity are common in neurological disorders such as autism and schizophrenia, two disorders reported to have altered microexon regulation.
Although not a cause of the disease, we know that changes in protein production can contribute to the symptoms of the disorder, so it is reasonable to study whether treatment to restore the arousal state in fish corrects or alleviates the symptoms in other species.”
Manuel Irimia, head of the Transcriptomics of Development and Evolution laboratory at UPF and CRG
This cAMP-regulated excitatory pathway is also implicated in anxiety and depression. That’s why Mackensen believes it’s worth continuing the research because “this could just be the tip of the iceberg.”
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