A closer look at the rapidly developing zebrafish embryo is helping neuroscientists to better understand the potential bases of brain disorders, including autism and schizophrenia.
Ohio State University researchers were interested in understanding the changes in neurological development that result from a genetic defect associated with neurological disease, in particular the loss of a gene called Protocadherin-19 or PCDH19. The link between mutation and brain disorders is well established, but the mechanisms of why one could lead to another have been a mystery.
The new study, published online this month in the journal eNeuro, indicates a "grouping" of cellular interactions in the brain that can disrupt normal development and brain health.
Scientists have discovered hundreds of genes that give rise to schizophrenia, autism and other brain disorders, but no one knows what is specific because of these genetic mutations. "
Chief researcher James Jontes, associate professor of neuroscience at the state of Ohio and member of the Neurological Institute of the University
"Our goal is to understand the cellular roles of these genes and how defects can lead to evolutionary changes in the brain."
Zebrafish, or Danio rerio, are small tropical freshwater fish that cater to scientists for a variety of reasons. Their embryos are transparent, they develop at warp speed and share a significant DNA fragment with people, allowing for a focused and enlightening examination of developmental changes that could have implications in attempts to combat human disease.
Jontes and his collaborator, student Sarah Light, wanted to see what happened neurologically when they introduced a PCDH19 mutation in zebrafish.
Using a high-powered microscope that allowed researchers to observe changes at the cellular level over time – a tool that Jontes did by itself – the researchers saw clear differences between embryonic development in normal wild type zebrafish and embryonic zebrafish in which had eliminated the PCDH19 gene.
"This is the first study that uses functional imaging at the single cell level to explore the effects of a mutation known to cause human neurological disease in a living organism, and we have seen obvious differences in the brain architecture of animals with the mutation, "said Jontes.
"This type of work has the potential to help us understand in more detail the relationships between genes and diseases including autism and epilepsy. We don't understand exactly what these mutations do to brain structure and development in human beings and if we can understand what they do in fish, which will take us a long way towards some answers ".
Neurons form networks in the brain that are essential for human development, thinking, function, behavior and emotions. In the altered zebra fish, the researchers were able to observe neuronal activity in great detail.
And, with the help of advanced mathematical analyzes designed to look for relationships between neurons and patterns in their activity, they saw that the neurological networks in the zebrafish with the mutation were more connected, or clustered, than in the brain of the common zebrafish.
The data was collected between three and six days after fertilization, a period of rapid growth and maturation in zebrafish. From the sixth day after fertilization, zebra fish larvae are already demonstrating behaviors such as hunting for food and swimming.
"We have seen many interconnections between neurons in the mutant zebrafish: we do not know exactly what it means, but it could mean that inappropriate connections occur between cells that normally would not interact, perhaps it becomes a problem when too many cells are incorporated into a network of neurons."
Jontes said that neuroscientists are fascinated by the fact that any number of genetic mutations have been linked to a particular disease, such as autism.
Work like this could help explain how each of these mutations results in a human disease, and this could be an important step towards better treatment, he said.
Ohio State University
Reference to the magazine:
Luce, S.E.W. & Jontes, JD. (2019) Multiplane Calcium Imaging reveals the disruption of the development of network topology in Zebrafish PCDH19 Mutants. eNeuro. doi.org/10.1523/ENEURO.0420-18.2019.
. (tagToTranslate) Brain (t) Genetic (t) Autism (t) Embryo (t) Fertilization (t) Fish (t) Gene (t) Genes (t) Mutation (t) Neurological disease (t) Neurons (t) Schizophrenia