From A to Z(ebrafish)
Scientists have identified more than 100 genes that are closely related to autism. Research has shown that these genes affect basic biological processes in the developing brain, such as nerve communication and regulating the expression of other genes. However, researchers have difficulty finding individuals with autism, however, due to the limited understanding of the basic biology of autism as well as the great clinical and genetic diversity.
But zebrafish offer many advantages for studying the function of autism genes in the developing brain and for identifying people who already use drugs. Zebrafish have the same genetic makeup as humans. They are also easy to manipulate genes, so it is possible to disrupt the activity of many risk genes at the same time; they produce many children at the same time; and larval zebrafish are easy to work with in the laboratory, making them amenable to large-scale clinical screens.
In previous research, Hoffman and his co-investigators found out how disrupting 10 different risk factors for autism in zebrafish affected basic sleep and emotional processing behaviors. For the new study, they wanted to use these behavioral “fingerprints” to predict and test certain drugs that “rescue” or change uncontrolled behavior in zebrafish carrying autism genetic mutations.
The researchers began to examine a total of 774 US FDA-drugs approved using independent analyzes of baseline sleep and auditory behavior in “wild-type” larval zebrafish that do not carry any mutations. Using statistical models, they made a database of 520 drugs that were not toxic and had significant effects on zebrafish behavior.
They then compared the behavioral fingerprints of zebrafish carrying the autism gene mutation to the behavioral fingerprints of drugs in a process called pharmaco-behavioral profiling. This allowed them to identify and test drug candidates predicted to rescue or reverse dysregulated behavior in zebrafish with mutations in two autism risk genes, SCN2A and WORSHIP1A.
Laying the foundation
Through their methods, the researchers revealed three major findings. First, they identified people using drugs that rescue the dysregulated sleep and emotional behaviors associated with autism genes. These drug candidates have identified central pathways associated with autism genetics, including estrogens, microtubules, mitochondria, and lipid metabolism.
Second, they found that the drug levocarnitine – which transports long-term fatty acids to the mitochondria – is the main rescue drug for two genes, SCN2A and WORSHIP1Aand showed that it rescues uncontrolled behavior, lipid metabolism pathways, and regional differences in basic brain functions in zebrafish. They also found that levocarnitine rescues network activity deficits in human pluripotent stem cell (hPSC)-derived glutamatergic (excitatory) neurons with mutations in these genes (pluripotent means the ability to produce many different types of cells).
Third, based on information about 520 US FDA-approved drugs, researchers developed a database that can be used to identify new patients with autism-related drugs. And they’ve created an open, searchable website with behavioral data for all 774 drugs tested, which they hope will facilitate drug discovery across different systems and platforms.
“Our findings lay the groundwork for investigating these drug mechanisms as potential targets for people with the autism gene mutation,” Hoffman said. “We can use our behavioral screening method to identify new drug candidates for the growing number of autism genes.”
The research team also includes co-author Zuoheng Anita Wang, a professor of biostatistics at the Yale School of Public Health (YSPH); Kristen Brennand, Elizabeth Mears and House Jameson Professor of Psychiatry at YSM; Priyanka Jamadagni, postdoctoral fellow at the Children’s Study Center; Yi Dai, Ph.D. candidate to YSPH; Yunqing Liu, Ph.D. a graduate of YSPH; and Hellen Weinschutz Mendes, a postdoctoral associate at the Children’s Study Center.
This work was supported by the National Institutes of Health, Binational Science Foundation, National Genetics Foundation, Simons Foundation, Spector Fund, Swebilius Foundation, Kavli Foundation, Howard Hughes Medical Institute Gilliam Fellowship, Autism Science Foundation, National Institute of Mental Health and National Institutes of Health Medical Scientist Training Program, and Interdepartmental Training Program of Yaya.
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