Could autism spectrum disorders (ASD) be caused by something as simple as an excess of chloride inside nerve cells? And could it be successfully treated with a common blood pressure medication?
A new study just published in Science reaffirms an earlier finding that ASD is related to an excess of chloride, and that a common diuretic may help treat or even prevent the disorder.
The excess of chloride is caused by a faulty switch that should be turned on just before birth, but is not in newborns who go on to develop autism spectrum disorder.
In late 2012, researchers found that treatment with the diuretic bumetanide produced significant behavioral improvement in children with autism or Asperger's syndrome.
Bumetanide is a strong diuretic, causing the body to increase the amount of water and salt that is excreted by the kidneys. It also blocks a chloride transport protein in the brain and significantly lowers the chloride level inside nerve cells. Parents were impressed enough with the results that almost all of them demanded to shift to (or continue with) bumetanide treatment.
Parents were impressed enough with the results that almost all of them demanded to shift to (or continue with) bumetanide treatment.
The chloride lowering is what the researchers believed was responsible for its beneficial effects in ASD children. But because they were unable to measure the chloride levels inside the neurons of the children, this was merely a theory.
In order to pinpoint how bumetanide works researchers had to go back to animals for further testing. The studies just published confirm the role of high chloride levels in producing autism in mice. An interaction among chloride ions, the hormone oxytocin and the neurotransmitter gamma aminobutyric acid (GABA) is responsible.
The environment of a fetus in the mother's womb changes abruptly when that fetus becomes a newborn. Chloride levels are typically high inside fetal neurons. This causes GABA, the major inhibitor present in people's brains, to excite nerve cells instead of calming them, as it normally does. This excitation is useful in the fetus because it promotes rapid development of the fetal brain.
But this activating role for GABA normally changes just before birth thanks to the hormone oxytocin. Oxytocin levels rise dramatically before birth, and one of the many effects of this rise is to lower the chloride level inside fetal neurons, a state that will persist after birth.
Oxytocin levels rise dramatically just before birth, and one of the many effects of this is to lower the chloride level inside fetal neurons, a state that will persist after birth.
The lowering of chloride in fetal, and newborn, neurons causes GABA to switch from acting as an exciter of nerve activity to an inhibitor of activity. But this switch will not occur if chloride levels remain high. So nerve cells will be overexcited and autism may result.
In the new study, researchers produced autism in mice by using mice with a genetic disorder, fragile X syndrome, a mutation most frequently associated with autism, or by injecting the pregnant mice with sodium valproate, a chemical known to generate abnormalities in children, including autism spectrum disorder.
The scientists recorded chloride levels inside neurons at various life stages of the mice and found that young and adult mice with autism do have a high chloride level inside their neurons and that these chloride levels do not fall at birth, as they should, but remain high.
If chloride levels remain high, nerve cells will be overexcited and autism may result.
When researchers gave a single bumetanide treatment to pregnant mice (both fragile X and valproate-treated) 24 hours before birth, chloride levels inside the neurons of newborn mice were restored to normal levels within several weeks which, in turn, corrected the autistic behavior of these mice once they reached adulthood.
Finally, when normal pregnant mice were injected with an oxytocin blocker, scientists were able to produce the symptoms of autism, both behavioral and electrical, in their offspring, symptoms identical to those found in the fragile X and valproate mice.
Taken together, these findings corroborate the 2012 study that found bumetanide lessens symptoms of autism and that it does so by lowering the concentration of chloride ion inside nerve cells.
There is no way to screen for autism in human fetuses at present, but the new study suggests that early treatment could help prevent this disorder from developing.