Birth hormone may control the expression of autism in animals

The scientific community agrees that autism has its origins in early life - foetal and/or postnatal. The team led by Yehezkel Ben-Ari, Inserm Emeritus Research Director at the Mediterranean Institute of Neurobiology (INMED), has made a breakthrough in the understanding of the disorder. In an article published in Science, the researchers demonstrate that chloride levels are elevated in the neurons of mice used in an animal model of autism, and remain at abnormal levels from birth. These results corroborate the success obtained with the diuretic treatment tested on autistic children by the researchers and clinicians in 2012, and suggest that administration of diuretics to mice before birth corrects the deficits in the offspring. They also show that oxytocin, the birth hormone, brings about a decrease in chloride level during birth, which controls the expression of the autistic syndrome.

This work is published in Science.

Neurons contain high levels of chloride throughout the entire embryonic phase. As a result, GABA, the main chemical messenger of the brain, excites the neurons during this phase instead of inhibiting them, in order to facilitate construction of the brain. Subsequently, a natural reduction in chloride levels allows GABA to exercise its inhibitory role and regulate the activity of the adolescent/adult brain. In many brain disorders (childhood epilepsy, cranial trauma, etc.), studies have shown abnormally high chloride levels. Having made various observations, Dr Lemonnier's team (Brest), and Yehezkel Ben-Ari's team at Inserm carried out a clinical trial in 2012, based on the hypothesis of high chloride levels in the neurons of patients with autism. The researchers showed that administration of a diuretic to children with autism (which reduces neuronal chloride levels) has beneficial effects . The results of the trial supported this hypothesis, but because high neuronal chloride levels could not be demonstrated in children with autism, it was not possible to prove the mechanism proposed or justify the treatment.

In the present study, the researchers therefore used two animal models of autism, a genetic model, Fragile X syndrome, which is the genetic mutation most frequently associated with autism, and another, generated by injecting the pregnant mice with sodium valproate, a product known to generate abnormalities in children, including autistic spectrum disorder.

A high level of chloride in the brain

For the first time, the researchers recorded the activity of neurons at the embryonic stage and immediately after birth in order to observe modifications in chloride levels. These observations showed that neuronal chloride levels are abnormally high in both young and adult animals used in the autism model. GABA strongly excites neurons, and the researchers recorded aberrant electrical activities in the brain, which persist in adult animals.

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