Estrogens alleviate hyperactivity in zebrafish with autism gene

January 28, 2016
Zebrafish

Research led by UCL, Yale and University of California, San Francisco has shown that the hormone estrogen alleviates the sleep disruption experienced by zebrafish genetically designed to help understand the biology of autism spectrum disorder (ASD).

The scientists set out to investigate the function of genes linked to autism and in humans by using zebrafish as a model system. They unexpectedly found that estrogens have a selective effect in calming hyperactive during the night which will help scientists to understand the brain pathways affected in ASD. The finding is also intriguing given ASD is four times more common in men than women.

Co-corresponding author, Dr Jason Rihel, UCL Cell & Developmental Biology, said: "We're surprised to see that estrogens in particular have such a selective effect in correcting hyperactive behaviour in our ASD fish model, and we're investigating this further to understand the mechanisms of this response. We don't know if the hormone is targeting single or multiple pathways, as is involved in lots of processes, but we're keen to find out."

The team discovered that a plant-derived estrogen, called biochanin A, and the human sex hormone, β-estradiol, were most effective at selectively stopping night time hyperactivity without affecting the daytime activity of the fish. The FDA approved drug risperidone, which was the first approved to treat irritability and aggressive behaviour in ASD patients, stopped hyperactivity but made fish less active during the day, suggesting estrogens are better at selectively targeting pathways that are relevant to ASD.

First author, Dr Ellen Hoffman, Yale University, said: "This research helps scientists to understand the function of an autism risk gene in the developing brain, which is important for understanding the biology of autism. The mechanism of action of the estrogens on zebrafish behaviour remains unknown and there is considerably more work to do before these findings can be applied to humans."

The study, published today in Neuron, used a simple animal model with genetic mutations to understand ASD at different levels, from cellular processes and brain circuitry, through to behaviour. Zebrafish were chosen as they have complex behaviours like sleep at a young age and are transparent, allowing brain development and activity to be visualised with markers. They are also amenable to drug screening, as compounds added to the water will enter the larval zebrafish brain.

Normal zebrafish were studied alongside those predisposed to seizures and due a mutation in the CNTNAP2 (often pronounced 'catnap') gene, which has been associated with human ASD. To identify specific processes involved in ASD-linked hyperactivity, the behavioural patterns of the mutant fish were compared to normal exposed to 550 psychoactive compounds. The compounds predicted to trigger or suppress the abnormal behaviour became candidates for follow-up experiments.

Dr Rihel added, "We used the drug screen as a tool to help identify the core mechanisms involved in ASD rather than to find new therapies. For example, drugs predicted to cause sleeplessness in the normal fish population might indicate the same pathways are affected in the mutant population. Conversely, those drugs that selectively promote sleep may hint at ways to rescue the mutant population from hyperactivity."Four of the top 10 compounds the screen predicted to supress sleeplessness were known to have estrogenic activity, suggesting estrogens as a whole class of molecules may have a positive effect on the mutant fish population. This was tested on both normal and mutant fish siblings using different doses of biochanin A and β-estradiol, which showed that both compounds selectively suppress the mutant night time hyperactivity.

The team plan to use this information to test the effect of estrogens in fish with other genetic mutations linked to ASD before progressing to mammalian models. These further studies will help map the pathways involved in ASD and understand the mechanism of action by which estrogens can specifically alter behaviour.

Explore further: Zebrafish model gives new insight on autism spectrum disorder

More information: Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the ASD Risk Gene, CNTNAP2, Neuron , February 17, 2016

Related Stories

Guanfacine shown safe and effective in autism treatment

August 31, 2015

Several different drugs are used for reducing hyperactivity and impulsive behavior in children, but most of these medications have not been well-studied in autism spectrum disorder. In a new article in the American Journal ...

Peri-op experience similar for children with, without autism

October 16, 2015

(HealthDay)—Children with autism spectrum disorder (ASD) have a significant difference in premedication type compared with children without ASD, although in other respects, their perioperative experiences are similar, according ...

People with autism run a higher risk of premature death

November 12, 2015

A registry study conducted at Karolinska Institutet and published in The British Journal of Psychiatry shows that the risk of premature death is about 2.5 times higher for people with autism spectrum disorder than for the ...

Recommended for you

A new window to understanding the brain

August 29, 2016

Scientists in recent years have made great strides in the quest to understand the brain by using implanted probes to explore how specific neural circuits work.

Special nerve cells cause goose bumps and nipple erection

August 29, 2016

The sympathetic nerve system has long been thought to respond the same regardless of the physical or emotional stimulus triggering it. However, in a new study from Karolinska Institutet published in the Nature Neuroscience, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.