Summary: Because autism spectrum disorder (ASD) is linked to over 100 different genes, a “one-size-fits-all” medication has proven impossible to find. However, researchers are changing the game by using zebrafish to create a “pharmaco-behavioral” map.
In a study, the team screened 774 FDA-approved drugs to see how they altered the behavior of larval zebrafish. By matching these drug “fingerprints” to the disrupted sleep and sensory behaviors of fish with specific autism mutations (like SCN2A and DYRK1A), they identified candidates—specifically the drug levocarnitine—that can “rescue” or reverse these symptoms.
Key Facts
- The Behavioral Fingerprint: Researchers identified specific sleep and sensory processing “glitches” in zebrafish carrying autism risk genes.
- FDA-Approved Shortcuts: By screening 774 already-approved drugs, the team created a database of 520 compounds that can now be “repurposed” to target specific genetic subtypes of autism.
- Levocarnitine Breakthrough: The study identified levocarnitine (a compound involved in fatty acid metabolism) as a top candidate for reversing behavioral and brain-activity deficits caused by mutations in SCN2A and DYRK1A.
- From Fish to Humans: The team confirmed their findings by testing levocarnitine on human stem-cell-derived neurons, where it successfully repaired excitatory network activity deficits.
- Open-Source Discovery: Yale has launched a searchable website containing the behavioral profiles of all drugs screened, allowing the global scientific community to accelerate drug discovery for other genetic conditions.
Source: Yale
In recent decades, the zebrafish has become one of the most valuable model organisms in scientific research. For a variety of reasons, including their genetic similarities to humans, these tiny tropical fish have helped researchers unlock secrets to diseases ranging from muscular dystrophy to melanoma.
Now, Yale researchers are hoping the zebrafish will do the same for autism spectrum disorder.
In a new study, a research team generated a database of 520 U.S. Food and Drug Administration (FDA)-approved drugs and their effects on basic larval zebrafish behaviors and then used the database to identify drug candidates that reverse disrupted behaviors in zebrafish carrying mutations in autism risk genes.
These drug candidates, the researchers say, might represent targets for people carrying mutations in specific autism risk genes.
“Because autism spectrum disorder is highly clinically and genetically heterogeneous, it is challenging to identify drug candidates and many new drugs under investigation are not effective in clinical trials,” said Ellen J. Hoffman, an associate professor at the Yale Child Study Center at Yale School of Medicine (YSM) and senior author of the new study.
“Our study highlights the importance of stratifying or subgrouping autism risk genes to identify potential drug candidates using a precision medicine-based approach.”
The study appears in the journal Proceedings of the National Academy of Sciences.
Scientists have identified more than 100 genes that are strongly associated with autism. Research has shown that these genes impact fundamental biological processes in the developing brain, such as neuronal communication and regulating the expression of other genes.
Researchers have struggled to identify pharmacological candidates related to autism, however, due to the limited understanding of the underlying biology of autism as well as its considerable clinical and genetic heterogeneity.
But zebrafish offer many advantages for studying the function of autism risk genes in the developing brain and identifying novel drug candidates. Zebrafish have a genetic profile that’s remarkably similar to that of humans. They’re also easy to manipulate genetically, so it’s possible to disrupt the function of multiple autism risk genes simultaneously; they produce large numbers of offspring at a time; and larval zebrafish are easy to work with in the lab, which makes them amenable to large-scale pharmacological screens.
In previous research, Hoffman and her fellow researchers identified how disrupting 10 different autism risk genes in zebrafish affected basic sleep and sensory processing behaviors. For the new study, they sought to leverage these behavioral “fingerprints” to predict and test specific drugs that “rescue” or reverse the dysregulated behaviors in zebrafish carrying mutations in specific autism risk genes.
The researchers first screened a total of 774 U.S. FDA-approved drugs using automated assays of basic sleep and sensory processing behaviors in “wild-type” larval zebrafish that don’t carry any mutations. Using statistical models, they generated a database of 520 drugs that weren’t toxic and had significant effects on zebrafish behavior.
Then they compared the behavioral fingerprints of zebrafish carrying mutations in autism risk genes to the drug behavioral fingerprints using a method called pharmaco-behavioral profiling. This allowed them to identify and screen drug candidates predicted to rescue or reverse dysregulated behaviors in zebrafish carrying mutations in two autism risk genes, SCN2A and DYRK1A.
Through their methods, the researchers revealed three major findings. First, they identified drug candidates that rescue dysregulated sleep and sensory processing behaviors associated with specific autism risk genes. These drug candidates showed central pathways relevant to these autism risk genes, including estrogens, microtubules, mitochondria, and lipid metabolism.
Second, they found that the drug levocarnitine — which transports long-chain fatty acids into mitochondria — is a top rescue drug for two genes, SCN2A and DYRK1A, and showed that it rescues dysregulated behaviors, lipid metabolic pathways, and regional differences in baseline brain activity in zebrafish.
They also found that levocarnitine rescues network activity deficits in human pluripotent stem cell (hPSC)-derived glutamatergic (excitatory) neurons carrying mutations in these genes (pluripotent refers to the ability to give rise to several different cell types).
Third, based on information about the 520 U.S. FDA-approved drugs, the researchers generated a database that can be used to identify new drug candidates relevant to autism risk genes. And they created an open-source, searchable website with the behavioral profiles of all 774 drugs screened, 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 individuals carrying mutations in select autism risk genes,” Hoffman said. “We can use our pharmaco-behavioral screening approach to identify new drug candidates for a growing number of autism risk genes.”
The research team also includes co-senior author Zuoheng Anita Wang, professor of biostatistics at Yale School of Public Health (YSPH); Kristen Brennand, the Elizabeth Mears and House Jameson Professor of Psychiatry at YSM; Priyanka Jamadagni, postdoctoral associate at the Child Study Center; Yi Dai, a Ph.D. candidate at YSPH; Yunqing Liu, a Ph.D. graduate of YSPH; and Hellen Weinschutz Mendes, a postdoctoral associate at the Child Study Center.
Funding: This work was supported by the National Institutes of Health, the Binational Science Foundation, the National Genetics Foundation, the Simons Foundation, the Spector Fund, the Swebilius Foundation, the Kavli Foundation, the Howard Hughes Medical Institute Gilliam Fellowship, the Autism Science Foundation, the National Institute of Mental Health and National Institutes of Health Medical Scientist Training Program, and the Interdepartmental Neuroscience Program at Yale.
Key Questions Answered:
A: Zebrafish share about 70% of their genes with humans, and their brains develop in a remarkably similar way. Because they are transparent as larvae and easy to genetically “tweak,” scientists can watch in real-time how a specific autism gene affects sleep, movement, and light sensitivity across thousands of fish at once.
A: Think of it like a biological “lock and key” system. The “lock” is the abnormal behavior caused by an autism gene (e.g., the fish can’t sleep). The “key” is a drug that produces the exact opposite behavior in healthy fish. By matching the drug to the mutation, researchers can “unlock” a return to normal brain function.
A: Not yet. While the results in fish and human stem cells are incredibly promising, this study provides the “groundwork” for clinical trials. The goal is precision medicine: only people with specific mutations (like SCN2A) would likely benefit from this specific drug.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this autism and genetics research news
Author: Fred Mamoun
Source: Yale
Contact: Fred Mamoun – Yale
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Pharmaco-behavioral profiling identifies suppressors of autism gene–associated phenotypes in zebrafish” by Priyanka Jamadagni, Yi Dai, Yunqing Liu, Hellen Weinschutz Mendes, April Pruitt, Suha Khan, Liang Yang, Tzu-Chieh Huang, Xiayuan Huang, P. J. Michael Deans, Novin Balafkan, Dejian Zhao, Gang Xu, Yihan Liu, Ningshan Li, Weimiao Wu, Sarah E. Fitzpatrick, Uma Neelakantan, Tianying Chen, Christina Szialta, David S. Jin, Cheryl M. Lacadie, Sheila Umlauf, Xenophon Papademetris, Yulia V. Surovtseva, Kristen J. Brennand, Zuoheng Wang, and Ellen J. Hoffman. PNAS
DOI:10.1073/pnas.2518846123
Abstract
Pharmaco-behavioral profiling identifies suppressors of autism gene–associated phenotypes in zebrafish
Pharmaco-behavioral screens in scalable in vivo systems have critical advantages for drug discovery relevant to large-effect autism spectrum disorder (ASD) genes.
Here, we establish a database and open-source website of the behavioral signatures of 520 US Food and Drug Administration (FDA)-approved drugs using high-throughput assays of basic sensory processing and arousal behaviors in larval zebrafish.
By leveraging the behavioral profiles of 9 large-effect ASD gene mutants, we identify enrichment of pharmacological mechanisms that anticorrelate with subgroups of ASD genes with shared behavioral phenotypes.
Screening of anticorrelating drugs in mutants of two ASD genes, SCN2A and DYRK1A, uncovers compounds that suppress mutant behavioral phenotypes. We identify estropipate, an estrogen receptor agonist, and paclitaxel, a microtubule inhibitor, as the top suppressors in scn1lab and dyrk1a mutants, respectively, and levocarnitine (LEVO), a mitochondrial modulator and carnitine supplement, as a top suppressor of both mutant behavioral phenotypes.
Finally, we find that LEVO rescues regional brain activity deficits and dysregulated lipid metabolic pathways in mutants, as well as signaling deficits in human pluripotent stem cell–derived glutamatergic neurons carrying mutations in SCN2A and DYRK1A, demonstrating conservation of drug rescue across systems.
Therefore, our study establishes a pharmaco-behavioral resource for precision medicine-based drug discovery, illuminating targets relevant to large-effect ASD genes.
