Drug reverses autism brain activity in mice, study shows
A generic blood pressure drug could prevent hyperactive brain cell firing associated with early stages of autism spectrum disorder, according to a new study.
Injecting pregnant mice with Bumetanide, a diuretic, appears to correct a developmental switch flipped during childbirth that reverses the firing characteristics of neurons in newborns, according to a study published online Thursday in the journal Science.
Bumetanide mimics the effects of oxytocin, a hormone released during labor that helps protect newborns from the stresses and complications of birth, the study found. That surge of oxytocin changes the way a neurotransmitter regulates neurons -- it no longer encourages the firing of neurons and becomes a kind of electrochemical brake in the adult brains.
Overly excited brain circuits are strongly linked with autism spectrum disorder, a disease that strikes an estimated 1 of every 88 children, causing them to have restricted interests, and impaired communication and social skills.
The drug was tested for only two types of autism that constitute a minority of cases of the perplexing disorder: a genetic mutation that causes Fragile X Syndrome, and autism sparked by prenatal exposure to the anticonvulsive valproic acid.
Researchers warned that further testing will be needed to determine both the efficacy of the drug in children and its potential for causing side effects. And because there is no way to diagnose autism risks to fetuses, it remains unlikely that such a therapy would be administered prenatally, as a prevention of autism.
“I’m not convinced that the hope is one day to be able to treat during pregnancy,” said neurologist Yehezkel Ben-Ari, of the French Institute of Health and Medical Research, the lead author of the study. “The hope is after birth, provided we have a good diagnosis.”
Early clinical trials in Europe have shown that the drug diminished autism symptoms among 60 children age 3-11. Further trials are underway, Ben-Ari said.
Researchers have long suspected the role of gamma aminobutyric acid, or GABA, but have not understood the intricacies of the “GABA switch” that is apparently thrown at birth, nor how it might be altered.
They focused on a kind of biochemical trade balance of chloride ions in neurons of the hippocampus. A surplus inside fetal neurons gradually decreases as a chloride exporter comes to dominate the equation, and oxytocin appears to mediate this change, according to the study.
“During delivery, you have important reactions that, if they fail, you have a higher likelihood of autism,” Ben-Ari said. “The delivery has a major priming effect on what is going to happen subsequently.”
But that priming doesn’t happen in mice with the Fragile X mutation or those exposed to valproic acid in utero, the researchers found. Chloride export was reduced in both. And GABA continued to excite the neurons of the newborns of both type rats, rather than inhibit them. This led to more active circuits, according to the study.
Bumetanide administered to pregnant mice changed the aberrant chloride profile in the the neurons of mice offspring, which also exhibited fewer autism-like characteristics in their vocalizations, according to the study.
Andrew Zimmerman, a pediatric neurologist at the Center for Autism and Neurodevelopmental Disorders at the University of Massachusetts Medical School in Worcester, said the findings were encouraging.
“They’ve further defined this GABA switch that we’ve suspected is present in normal brain development but is probably abnormal in autism brain development,” Zimmerman said. “This is direct confirmation, as close as you can get in animals.”
Zimmerman noted that 80% of autism cases arise from unknown causes unrelated to Fragile X syndrome or exposure to valproic acid. Still, he added, the fact that two widely different causes of autism showed a chloride imbalance suggests that this may be a common denominator in other cases.
