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Subspecialties Neuro-ophthalmology, Basic & Translational Research

Eye to Eye

Researchers have long agreed that the zebrafish represents a great model organism when it comes to studying neural activity. As we share approximately 70 percent of the same genes, as well as the same basic vertebrate brain structure and neurochemistry, it is possible to find an equivalent in zebrafish for most human disease genes.

It was while studying one gene in particular that researchers made a connection: developmental brain abnormalities may play a role in people who cannot control their eye movements. The gene in question? “Down Syndrome Cell Adhesion Molecule-Like 1 – or dscaml1 – a gene expressed during nervous system development in humans,” says Albert Pan, an associate professor at the Fralin Biomedical Research Institute at VTC in Roanoke, VA, USA.

Interestingly, many of the characteristics seen in the zebrafish dscaml1 mutants were similar to those associated with human ocular motor apraxia

Though dscam1 deficiency has been linked to autism spectrum disorder in the past, its contribution to behavioral deficits remains largely unknown. In a bid to understand more, Pan and his team began tracking the eye movements of larval zebrafish in response to controlled visual stimuli. “In the absence of dscaml1, zebrafish developed deficits in many aspects of eye movement, including slower saccades – a type of fast, ballistic eye movement – and frequent pauses during optokinetic response,” says Pan. But that was not all.

When the researchers used two-photon calcium imaging to visualize neuronal activity in the living animal’s brain during saccades, they were able to identify impaired neural pathways that correspond to the behavioral deficits. Interestingly, they found that many of the characteristics seen in the zebrafish dscaml1 mutants were similar to those associated with human ocular motor apraxia – a developmental deficit in saccade generation that makes it difficult for patients to read or perform other tasks that require frequent gaze shifting.

Though the cellular mechanism for these behavioral deficits remains unexplored, the team have a few ideas. “As dscaml1 is a cell adhesion molecule that regulates the wiring of the nervous system, it may regulate the assembly of the circuit controlling eye movement,” says Pan. “Genetic lesions of Dscaml1 in humans have been linked to autism spectrum disorders; our study provides the first clues about how loss of dscaml1 affects vertebrate behavior.” A breakthrough – but to what end?

The multi-university team believes the zebrafish dscaml1 mutant offers a promising opportunity to understand how common vertebrate behaviors develop – and change – in normal and pathological conditions. “It is intriguing that the dscaml1 mutants are phenotypically similar to human ocular motor apraxia, a developmental disorder characterized by early-onset saccade initiation failure,” Pan muses.

“The genetic causes of ocular motor apraxia are still largely unknown, and it will be exciting to see whether there is a genetic link between ocular motor apraxia and dscaml1 mutations. We are currently working to understand the physiological changes in zebrafish dscaml1 mutants, with the hope that some affected physiological pathways may be good targets for treating eye movement disorders in the future.”

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  1. M Manxiu et al., “Zebrafish dscaml1 deficiency impairs retinal patterning and oculomotor function”, J Neurosci, 4, 1783 (2019). PMID: 31685652.

About the Author

Phoebe Harkin

Associate Editor of The Ophthalmologist

I’ve always loved telling stories. So much so, I decided to make a job of it. I finished a Masters in Magazine Journalism and spent three years working as a creative copywriter before itchy feet sent me (back)packing. It took seven months and 13 countries, but I’m now happily settled on The Ophthalmologist, where I’m busy getting stuck into all things eyeballs.

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