Levocarnitine: A Compound That “Reprograms” Neurons in Autism

What if existing medications could be repurposed to treat autism more precisely? Using genetically modified zebrafish, scientists have managed to link specific mutations to potential treatments, and a common compound has shown surprising results. This discovery could be an important step towards personalized medicine in autism.

Autism spectrum disorder is a complex condition that affects brain development, influencing communication, behavior, and how a person perceives the world. In recent years, scientists have identified several genes associated with autism, but transforming this genetic knowledge into effective treatments remains a major challenge.

This is because knowing which gene is involved does not automatically mean understanding how to correct the effects of this alteration in the brain. The study presented seeks precisely to shorten this path, connecting genetics, behavior, and potential treatments in an innovative and accessible way.

The researchers started from a simple but powerful idea: if different genetic mutations cause specific changes in behavior, perhaps it is possible to find medications that reverse these patterns.

To achieve this, they needed an experimental model that was fast, reliable, and allowed them to test many compounds simultaneously. That's where zebrafish came in, an organism widely used in science because its biological systems share several similarities with humans, especially in the development of the nervous system.

The scientists used zebrafish larvae genetically modified to carry mutations associated with autism. These larvae were then observed in tests that evaluated two main aspects: how they responded to sensory stimuli (such as light and sound) and how they regulated states of alertness, such as activity and rest.

These behaviors function as a kind of "fingerprint," revealing how the brain is working. By analyzing these patterns, the researchers were able to identify specific alterations caused by each genetic mutation.

Next, the researchers tested hundreds of drugs already approved for human use. More than seven hundred compounds were analyzed, of which more than five hundred showed measurable effects on the fish's behavior. Each drug generated a new "behavioral signature," allowing them to compare its effects with the patterns observed in the mutated larvae.

Zebrafish Larvae

The central idea was to find drugs whose effects were the opposite of those caused by the mutations, that is, that could potentially correct the observed alterations.

With this enormous database in hand, the scientists began to cross-reference information. They compared the behavioral profiles of fish with genetic mutations to the profiles generated by the drugs.

When they found a compound that reversed the altered pattern, for example, normalizing a sensory response or an activity pattern, it became a promising candidate. This process was applied especially to mutations in important genes linked to autism, such as those responsible for regulating the electrical activity of neurons and brain development.

To ensure that the results were not exclusive to fish, the researchers went a step further. They used human stem cells to create neurons in the laboratory that carried the same genetic mutations studied in the fish. These neurons presented problems in communication with each other, especially in excitatory networks, which are fundamental to brain function.

When applying one of the identified compounds, levocarnitine, scientists observed a significant improvement in the activity of these cells, suggesting that the drug's effect may also be relevant in humans.

Among all the compounds tested, levocarnitine stood out for its ability to improve both the behavior of fish and the activity of human neurons. This is especially important because this substance is already known and used in other medical contexts, which could accelerate its potential clinical application.

This work represents an important advance in the search for personalized treatments for autism. By integrating genetics, behavior, and pharmacology, the researchers created a platform that allows for the rapid identification of drugs with therapeutic potential.

Furthermore, by making the data available in an open database, they enable scientists worldwide to continue exploring this information. In the future, this approach may help develop more specific and effective treatments, tailored to the individual characteristics of each patient.

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Pharmaco-behavioral profiling identifies suppressors of autism gene–associated phenotypes in zebrafish

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. March 16, 2026 123 (12) e2518846123

DOI:10.1073/pnas.2518846123

Abstract:

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.