A Yale-led team of scientists found that estrogens could reverse abnormal behavior in zebrafish carrying a mutation in a gene strongly associated with autism and seizures in humans, they reported Jan. 28 in the journal Neuron.
The effect of a female hormone intrigued scientists because autism is four times more common in males than females.
“We were very surprised by this finding,” said Antonio Giraldez, professor of genetics and co-senior author of the paper. “Our study shows the strength of using zebrafish mutants as a platform to identify compounds with relevance to autism, though there is much more work to do before this can be applied to humans.”
The research team led by Ellen Hoffman, assistant professor at the Yale Child Study Center, along with Giraldez, Matthew State at the University of California-San Francisco, and Jason Rihel at University College London — focused on the gene CNTNAP2. A mutation in this gene in some Amish families has previously been shown to cause a form of autism and epilepsy.
The team studied the effect of disrupting this gene in zebrafish, which are transparent and allow scientists to visualize key processes during brain development. Mutations in zebrafish cntnap2 result in a loss of inhibitory neurons in the developing brain and cause the fish to become hyperactive at night, they found.
The team compared the behavior of normal fish exposed to hundreds of approved drugs to the behavior of fish carrying the mutation and predicted which drugs could trigger or suppress the abnormal behavior. They found that drugs that act like estrogens were able to restore normal activity levels at night in the mutant fish.
“These compounds did not act like a sedative, rather they reversed the abnormal behavior in a specific manner,” Giraldez said.
“This research helps scientists understand the function of an autism risk gene in brain development, which is important for understanding the biology of autism,” Hoffman said.
Giraldez emphasized that the mechanism of action of the estrogenic compounds in zebrafish is still unknown and further studies in mice are a critical next step before this work can be applied to humans.