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U. study uses tadpoles to explore link between VPA, hyperconnected brain

Tadpole experiments have implications for neurodevelopmental studies, autism research

In a recent study, University researchers used a tadpole model to better understand the effects valproic acid — an anti-epilepsy drug commonly known as VPA — has on neurodevelopment and behavior. VPA has long been known to have deleterious effects on fetuses, such as increasing the risk for developing autism. The study shows specific parallels between behavioral deficits in tadpoles exposed to the drug and humans with autism.

“We don’t have an ethical way of accessing an active, functional brain” in humans, but tadpoles offer a convenient animal model for neurodevelopmental studies, said Eric James GS, lead author of the study. A specific benefit to using tadpoles is that the rearing medium they grow up in is similar to the embryonic fluid of other animals, he added.

The team used electrophysiology to measure VPA’s effects on the tadpoles, James said. Researchers patched a glass electrode onto an individual brain cell to measure its activity. By observing individual brain cells, they also examined how the brain cells act together, he added.

Exposure to VPA causes the brain to become hyperconnected even though individual neurons become less excited. This tends to correlate to an immature brain, James said.

“It is an emerging view that autism stems from hyperconnectivity of the brain,” said Carlos Aizenman, associate professor of neuroscience and senior author of the study. The brain becomes garbled when hyperconnected, causing it to function abnormally, he added.

The researchers tested the tadpoles by repeatedly startling them and recording their responses. The tadpoles that were not exposed to VPA jumped the first time but reacted less and less during subsequent trials. But the tadpoles that were exposed to VPA were still very sensitive to being startled even after the first time, Aizenman said.

The social behavior of tadpoles was also hindered by VPA exposure, Aizenman added. It is believed that tadpoles sense other tadpoles’ locations through vibrations from their swimming patterns, leading them to swim close to each other in schools, Aizenman said. The tadpoles that were exposed to VPA were often found swimming alone, indicating that they likely cannot process that information correctly.

“The point of this study isn’t to highlight the deleterious effects of VPA, but instead to use VPA as a tool to better understand neurodevelopment,” James said. The brains of vertebrates such as tadpoles and humans are similar in that the brain organization, genes involved in brain functions and developmental processes in which the brain gets wired are the same, Aizenman said. But the brains of tadpoles and humans are not identical, so it is important to recognize that an animal model will have its limitations, he added.

“Even if we can’t apply it directly, it can help us understand step by step how it happens in humans,” said Florence Roullet, a post-doctoral fellow at McMaster University, who was not involved in the study.

With a rodent model, tadpole model and human model, we can gain a better understanding of the process by which VPA causes neurodevelopmental problems, James said. By finding common ground among the animal models, neuroscientsists can start identifying molecules that play important roles in these disorders.

The combined findings can also lead to a better understanding of whether neurodevelopmental disorders caused by environmental and genetic risk factors have the same mechanisms as drug-induced ones, James said.

Studies like these are “important for research on humans because they open the door to understand molecules that could have similar effects,” Roullet said.


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