Study sheds light on mutation involved in autism, schizophrenia

A close look at the rapidly developing zebrafish embryo is helping neuroscientists better understand the potential underpinnings of brain disorders, including autism and schizophrenia, according to a new study by researchers at Ohio State University and published in the journal eNeuro.

Using a high-powered microscope that allowed the researchers to watch cellular-level changes over time, designed by lead researcher James Jontes, PhD, an associate professor of neuroscience, the researchers saw clear differences between embryonic development in normal wild type zebrafish and embryonic zebrafish in which they'd eliminated the PCDH19 gene.

Neurons form networks in the brain that are essential to human development, thought, function, behavior, and emotion. In the altered zebrafish, the researchers were able to observe neuron-level activity with great detail.

The researchers used advanced mathematical analysis designed to look for relationships between the neurons and patterns in their activity, finding the neurological networks in the zebrafish with the mutation were more connected, or clustered, than in the brains of ordinary zebrafish.

The data was collected between three and six days after fertilization, a period of rapid growth and maturation in zebrafish. By the sixth day after fertilization, zebrafish larvae are already demonstrating behaviors, such as hunting for food and swimming.

Zebrafish are small tropical freshwater fish that appeal to scientists for a handful of reasons. Their embryos are transparent, they develop at warp speed, and they share a significant chunk of DNA with people, allowing for an expedient and enlightening examination of developmental changes that could eventually have implications in attempts to thwart human disease.

"We saw lots of interconnections between neurons in the mutant zebrafish,” said Jontes in a statement by the university. “We don't know exactly what that means, but it could mean that inappropriate connections are occurring between cells that wouldn't normally interact. Maybe it becomes a problem when too many cells are incorporated into a network of neurons."

Scientists have discovered hundreds of genes that give rise to schizophrenia, autism, and other brain disorders, but nobody knows what specifically goes wrong as a result of these genetic mutations, Jontes said.

"This is the first study to use functional imaging at a single-cell level to explore the effects of a mutation known to cause human neurological disease in a living organism,” Jontes said, “and we saw obvious differences in the brain architecture of the animals with the mutation.”

Jontes said neuroscientists are intrigued by the fact that any number of genetic mutations have been linked to a given disease, such as autism. He said work like this could help explain how each of those mutations results in human illness, and that could be an important step toward better treatment.

"This type of work has the potential to help us understand in more detail the relationships between genes and diseases including autism and epilepsy.” he said. “We don't understand exactly what these mutations do to brain structure and development in humans and if we can figure out what they do in fish, that will get us a long way toward some answers."