Drug that affects brain chloride levels staves off symptoms in mice and rats
Curbing chloride in nerve cells could combat symptoms of autism, a study of rats and mice suggests. The results may explain why a small group of children with autism seemed to improve after taking the common diuretic bumetanide in an earlier study.
The new details of how bumetanide works, published in the Feb. 7 Science, provide important clues about how autism spectrum disorders arise in a developing brain, says Susan Connors, an autism specialist at Massachusetts General Hospital for Children in Boston who was not involved in the study. If extended to people, the results would point to a concrete biological difference in the brains of people with autism, one that could be targeted with drugs. That would be “a great step forward,” says Connors.
In the new study, the drug curbed autismlike behaviors in pups when given to pregnant mice and rats a day before delivery. But Connors and others caution that it’s too soon to try the diuretic on infants or pregnant women.
In 2012, researchers led by Yehezkel Ben-Ari of INSERM, the French National Institute of Health and Medical Research, and colleagues published results of a clinical trial that found bumetanide seemed to improve children’s symptoms of autism or Asperger’s syndrome. But the scientists didn’t know how the drug worked. “We give a diuretic and the kids feel better, but you have no idea of the mechanism,” Ben-Ari says.
To find out, the researchers turned to two animal models of autism: mice that carry a mutation that causes behaviors similar to those seen in people with the autism spectrum disorder called fragile X syndrome and rats exposed during gestation to the chemical valproate, which results in autismlike behaviors.
In addition to behaviors such as abnormal vocalizations, these mice and rats had a pronounced brain abnormality, the researchers found: Their neurons had too much chloride. And this chloride abundance interfered with a critical brain event that happens during birth.
During gestation, the neurotransmitter GABA makes brain cells very excitable and active. After birth, GABA does the opposite, instead calming nerve cells. That process is an important rite of passage for the developing brain, and earlier work suggested that it goes awry in people with autism.
Too much chloride prevents this shift, leaving the brain in an immature, excitable state, Ben-Ari and colleagues report. But giving pregnant mice and rats a dose of bumetanide a day before delivery prevented abnormal behavior by reducing the chloride levels in pups’ nerve cells and allowing their brains to undergo the GABA reversal.
“It’s a very simple way to flip a switch,” says J. Jay Gargus, director of the University of California, Irvine Center for Autism Research and Translation.
Chloride levels can be reduced another way too. The hormone oxytocin, known for its role in labor and promoting social bonding, lowers chloride in brain cells. Too little oxytocin right before rats’ birth resulted in pups born with overly excitable brains, the researchers found.
Oxytocin’s relationship to autism is contentious. Some researchers have found a link between labors induced with oxytocin and elevated rates of autism. But the new results suggest that too little oxytocin during delivery might increase autism risk.
It’s not known when bumetanide, if it works in humans as it does in rodents, would be most effective. Autism researchers generally agree that the earlier treatment starts, the better the outcome. As scientists hone their ability to spot autism in very young babies (SN Online: 11/6/13), treatments such as bumetanide might become feasible even during pregnancy. Scientists don’t know whether bumetanide would work well on older children.
Many other questions remain before bumetanide can be used to treat or prevent autism in people. The drug is a potent diuretic that treats disorders including heart failure and high blood pressure. While it and oxytocin may turn out to be powerful avenues for further research, it’s unclear how the drugs might influence the growing brain and body. “A lot of things are changing in the first and second year of life, and you have to be cautious that you don’t cause more problems,” says clinician Randi Hagerman of the University of California, Davis Health System in Sacramento, Calif., who was not involved in the study.
Gargus also urges caution. Bumetanide is available to anyone with a prescription, but it hasn’t been extensively studied in children. “These are powerful medications,” he says.
Ben-Ari and colleagues have started another clinical trial of bumetanide that includes 80 children with autism ages 2 to 18. The team hopes to conclude the trial by the end of the year.
S. Tyzio et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science. Vol. 343, February 7, 2014, p. 675. doi: 10.1126/science.1247190.
L. Sanders. Autism may be detectable in baby’s first months of life. Science News Online, November 6, 2013.
L. Sanders. One problem, many paths. Science News. Vol. 180, August 13, 2011, p. 20.
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