What studying worms, flies and fish says about autism – Spectrum

Scientists have also studied the nighttime rituals of another autism model: zebrafish (Danio rerio). Gene-editing techniques enable scientists to create zebrafish with autism-linked mutations, and then they can easily assess how the mutations effect behavior. We can take our fish larvae at 5 days old they have this complex range of behaviors we can easily pipette them into the wells of a 96-well plate, and then track different aspects of their locomotor activity, Hoffman says. The design offers the high throughput and easy replicability of a cell culture study, with the ability to gauge effects on animal behavior.

As a postdoctoral researcher, Hoffman tracked the behavior of 5-day-old zebrafish larvae lacking the autism-linked gene CNTNAP2 and found that they are hyperactive at night. The fish also have fewer-than-usual inhibitory neurons, which dampen neural activity, in the forebrain, replicating findings in mice lacking the same gene and adding heft to the relevance of the fish as an autism model.

Zebrafish are a useful tool for screening potential drugs for autism because chemical compounds can be added directly to the water the fish swim in. In their CNTNAP2 study, published in 2016, Hoffman and her colleagues tested the effects of 14 drugs on the larvae and showed that certain forms of the hormone estrogen can reverse the larvaes hyperactive behavior.

The animals are small and relatively inexpensive, so the team can use them to study the effects of many autism-linked genes in parallel. Hoffmans team is looking at brain activity, movement and sleep-wake cycles across multiple lines of zebrafish with mutations in the fish equivalents of 10 autism-linked genes, including CHD8, CNTNAP2, DYRK1A, GRIN2B and SCN2A. The researchers aim to identify shared characteristics across strains and to identify drugs that could reverse alterations in their behavior.

The CNTNAP2 zebrafish developed in Hoffmans lab are slated to appear on a list of validated zebrafish models curated by the Simons Foundation Autism Research Initiative (SFARI). (Spectrum is an editorially independent publication funded by SFARI.) The goal of that list is to make zebrafish research more reliable by steering researchers toward models that pass a test of genetic quality, says SFARI senior scientist Brigitta Gundersen.

Its all a matter of matching your question to the advantages and disadvantages of your model system. Ethan Scott

Zebrafish larvae have another advantage: They are transparent for the first several days of life. As a result, researchers can see the larvaes internal organs, including the gut, enabling them to visualize the effects of autism mutations on gut function, which is often disrupted in autism. In the larvae, researchers can observe the rhythmic movements of the gut muscles, and food moving through the digestive system. Things play out right in front of you, says Julia Dallman, associate professor of biology at the University of Miami in Coral Gables, Florida.

In studies published in 2019 and 2020, Dallmans team showed that the gut muscles contract, and food moves through the gut, unusually slowly in zebrafish with mutations in SYNGAP1 or SHANK3. In people, mutations in these genes are linked to both autism and gastrointestinal distress, including constipation and acid reflux. When we initially set out to look at gut function in these models, my expectation was that [alterations] would be subtle, Dallman says. Its not subtle at all. Her teams studies suggest that slightly different mechanisms underlie gut problems in the two fish strains, so treatment of constipation in autism may not be one size fits all. Dallman plans to test the effects of drugs on both gut function and behavior in the fish, to aid in the search for autism medications that dont worsen constipation, she says.

The transparency of zebrafish larvae also puts early brain development on display. Using specialized microscopes, researchers can visualize the activity of individual neurons and, because the fish are small, simultaneously track the activity of every neuron in the brain. Youre just observing the brain in an intact, alert, behaving, perceiving animal, says Ethan Scott, who studies sensory processing in zebrafish at the University of Queensland in Brisbane, Australia.

Zebrafish have a more similar brain structure to humans than do invertebrate models, Scott says. And although the fish lack a cerebral cortex, the structure at the surface of the human brain, they are useful for studying circuits in other parts of the brain. Its all a matter of matching your question to the advantages and disadvantages of your model system, Scott says.

Scott is using zebrafish larvae with mutations in autism-linked genes to investigate alterations in sensory processing in autism. He and his colleagues are monitoring their brain activity in response to images shown on a computer screen, and to sounds of varying loudness. In a 2020 study, his team showed that zebrafish lacking FMR1, the gene mutated in fragile X syndrome, are hypersensitive to sound. And in four regions of the brain, their neurons react to sound with more frequent or stronger bursts of activity than those in typical fish. The work may help explain sensory hypersensitivity in autism, Scott says.

Here is the original post:
What studying worms, flies and fish says about autism - Spectrum