Small Fish, Big Insights: An Unlikely Model for Studying Neurodevelopmental Disorders

Could the key to certain brain disorder treatments lie in an aquarium? While different from us, fish may help us understand the human brain’s intricacies. 

Zebrafish, tropical freshwater fish named for their horizontal stripes, are genetically quite similar to humans. For “about 70% of human genes, you can find an orthologous gene in zebrafish,” says Dr. Summer Thyme, a researcher at UMass Chan Medical School, referring to how most zebrafish genes correspond to human genes. Zebrafish are vertebrates like humans, so they share many internal physiologies (like similar brains and spinal cords). 

Taking advantage of these similarities, scientists use zebrafish to study neurodevelopmental disorders such as autism or Down syndrome. These genetic brain disorders are caused by mutations in DNA and impact the development of the nervous system. Autism is characterized by difficulties in interaction and behavior and usually develops between 18 and 24 months of age. Down syndrome causes delays in physical and neurological development and can be detected in the womb.

Zebrafish are emerging as advantageous for early analysis and experimentation. Their eggs and embryos are transparent and develop outside the womb, allowing for clear visualization of early growth. They are cheap and easy to store, making them convenient for research. 

Hundreds of drug molecules and genes can be tested on zebrafish quickly, so further examination can be done on mice for more specific visualization. With mice, it can take “a couple [of] years to study one gene in detail,” says Thyme. Zebrafish, however, can provide “information about a hundred genes in the same time.”

First, scientists must use genome sequencing to pinpoint human genes that contribute to a disorder. Then using CRISPR-Cas9 gene-editing technology, they can “knockout,” or disable, risk genes in zebrafish, so they exhibit the disorder’s characteristics. Think of it this way: If a machine that attaches the soles in a shoe factory was turned off, the resulting shoe would be significantly different from those with soles. Similarly, this “knockout” process simulates a disorder. The mutant fish can be compared to unaltered fish to analyze differences in behavior and physiology. They can also be mass-tested with drugs to explore treatment options. 

In the case of autism, Thyme found that one gene affected the development of neurons that produce the hormone oxytocin, which facilitates social bonding. Hence, children with autism often form relationships differently than their peers. Another batch of zebrafish had an imbalance in excitatory and inhibitory neurotransmitters (chemical messengers between neurons), which during normal function allow or block chemical signals in nerves, respectively. Some also displayed altered sleep patterns and sensitivity differences, altered anatomies (one batch had atypical brain sizes), and social-interaction deficits. Learning about these differences can help researchers pinpoint the genetic causes behind autism to better understand its development and presentation in humans.

Zebrafish can also be used to study Down syndrome. Down syndrome is caused by an extra copy of chromosome 21, yet it is not clear which genes contribute to the brain developmental differences observed in people. Some cases in humans only have a partially duplicated chromosome, indicating that a small set of genes is likely most critical. Thyme’s lab is trying to narrow down which genes by adding different copies to the zebrafish and then determining their effects on brain development and function. When the gene DYRK1A, linked with Down syndrome, was altered in zebrafish, neurological delays and microcephaly, a birth defect causing a smaller head, were observed. 

Using these zebrafish models, Thyme hopes to be able to explore the effects of mutations in different genes to analyze the genetics of neurodevelopmental disorders. Not all cases of neurodevelopmental disorders in humans are the same. Her research introduces a possible method for not only explaining differences but also exploring different treatments. She aims to implement learning and memory tests to assess cognitive abilities rather than relying only on behavior and morphology (form, shape, structure). 

“There’s so many possible different genes and mechanisms that could ultimately lead to what looks like the same disorder,” says Thyme. “Being able to dissect all of these individually is really hard but with [zebrafish] we can [begin to] get at that because we can do so many.” 

Thyme continues to rely on zebrafish models to better understand neurodevelopmental disorders and survey potential drug treatments. She is grateful that such simple models can reveal so much about the complexity of the human brain.