First published in Médecine & Sciences
The data on autism are well known: the impact is strong, because -with an incidence of 1,4%- this disease affects communication, which an essential function at the heart of our modern societies. And yet, despite the successive “autism plans” and the sometimes huge sums invested (hundreds of millions of dollars in the United States), the pathogenesis of this disease is poorly understood and no pharmaceutical treatment is approved by European or American authorities. It seems to me that in addition to the complexity and heterogeneity of autism, genetic reductionism and neglect of brain development explain our relative failure.
This is because autism is generated in utero. Epidemiological data show an increase of its incidence after viral or bacterial infections, in utero inflammation, prematurity, scheduled cesarean sections, use of drugs, including the infamous depakine, endocrine disruptors or exposure during pregnancy to pesticides, including at a distance of 1,5 km from spray fields (more than the 3-5 meters recommended by policies). The hundreds of genetic mutations identified also contribute, but with a low penetrance and a poorly estimated occurrence (15/20%?), limiting their diagnostic value and above all having limited therapeutic value. Indeed, any pathological event in utero, whether genetic or non-genetic, produces sequelae by modifying cerebral growth, brain maturation and the formation of neural networks that will disrupt cerebral functioning, at the origin of the autistic syndrome. Thus, the growth of the cranial perimeter follows a gradual upward curve, which slows down shortly before birth, perhaps in preparation for this vulnerable period. Experimental data from our work suggests that this slowing down is abolished in autism, as brain structures like the hippocampus or neocortex continue to grow during birth. The cranial perimeters of children and adolescents with autism are sometimes larger, even of the “megalencephalic” type, suggesting a change in growth in utero in accordance with clinical observations by the Bonnet-Brihault team [1]. Post-mortem studies also show an increase in the number of neurons in certain cortical regions, consistent with intrauterine pathogenesis. As a result, autism starts during pregnancy and childbirth and we are not able to make a diagnosis at this stage yet. To understand and treat autism, I would rather focus our efforts on determining the sequence of alterations produced by the first event in brain development rather than identifying new genetic mutations.
In this context, the first fundamental notion to remember is that the immature brain is not a small adult brain. The movements in utero are not voluntary but reflex, the cortical signals supposed to trigger them occurring after the movement and not before. The retinal waves generated by visual stimulation in a premature baby do not allow to see. They are later transformed into rapid responses consistent with vision. All voltage-sensitive or transmitter-sensitive ionic currents, like the discharge patterns they generate, are specific of the immature brain and later replaced by a plethora of adult discharge patterns. It is as if the roles of these immature and adult discharge patterns differ. With my colleague and friend Nick Spitzer, we proposed, in the early 2010s, the concept of “checkpoint”: immature activities make it possible to validate or invalidate the wiring of networks, wiring that is by no means automatic. Genes and activity operate in series, and very clever whoever can separate them!
If the construction of the brain involves specific processes, the intrauterine disease will produce its effects through specific mechanisms in the immature brain. The causative pathological event in utero, whether genetic or environmental, causes lasting sequelae, which manifest themselves as symptoms, sometimes years later. The concept of “neuro-archeology” [2] proposes that these pathological inaugural events deviate the maturation sequences, resulting in brain malformations and misplaced or poorly connected neurons, responsible for the autistic syndrome. I thus suggested that misplaced neurons do not “mature” and generate ionic currents and immature discharge patterns in the adult brain, which directly cause the disease. The study of migratory disorders associated with infantile epilepsies confirms this hypothesis, the seizures being generated by these regions endowed with immature neurons. These observations imply, therapeutically, that drugs or comfort molecules can have different effects on the mother and her embryo / foetus. Thus, depakine, an effective antiepileptic in adults, causes major malformations during pregnancy. Its use in rodents provides an excellent animal model of autism. The concept of neuro-archeology opens new possibilities for treatment because molecules that selectively block these immature activities could alleviate the severity of the disease, with few side effects. This approach is less ambitious than gene therapy, which aims to cure the disease, but more realistic, because it is unlikely that the “good gene” will be able to bring the brain back to the ante situation, with migration and recovery of the connection of neurons with their targets.
I will illustrate this with experimental research undertaken three decades ago that could lead to a new treatment for autism. Initially, there is the discovery of elevated levels of intracellular chloride [(Cl–)i] in immature neurons, which results in a change in the polarity of gamma-amino-butyric acid (GABA), which, instead of behaving as the main mediator of inhibition, promotes the excitation of target neurons. This property, respected throughout evolution, is at the origin of the trophic actions of GABA. Then, we observed that the high levels of [(Cl–)i] decrease during parturition and childbirth under the action of the hormone oxytocin, which also has the role of inducing labor and uterine contractions. This action of oxytocin has neuroprotective effects during this highly vulnerable period. However, this drop in [(Cl–)i] during parturition is abolished in many animal models of autism (depakine in utero, fragile X syndrome, Rett syndrome or intrauterine inflammation), suggesting a decrease in actions of the hormone. Maternal administration of bumetanide, which reduces [(Cl–)i] levels and restores GABAergic inhibition, just before birth, reduces the severity of autism in the newborn [3, 4]. These data suggest that parturition and childbirth may alleviate or worsen an intrauterine pathological process, with very long-term consequences. The implications are significant, given the role of oxytocin at birth on the attachment between mother and baby and the effects of premature births and scheduled caesarean sections on the increased incidence of autism.
The implications are also therapeutic. In fact, high [(Cl–)i] levels and reduced GABA inhibition persist in autism but also in various other conditions: spinal cord injuries, cranial traumas, cerebrovascular accident, chronic pain, epilepsy, trisomy 21, Huntington’s disease or Rett syndrome. This Prévert-style list suggests that in autism, as in many stroke / disease, GABAergic inhibition is achieved with an “immature reversion”. Suddenly, it becomes possible to reduce the severity of the autistic syndrome, by reducing the levels of [(Cl–)i], with agents such as bumetanide, a selective antagonist of the main importer of chloride. With my colleague and friend Éric Lemonnier, we decided to try this approach in the treatment of autism, based on the observation that benzodiazepines, whose action involves GABA, often have paradoxical effects in children with autism, suggesting the possible existence of high levels of [(Cl–)i]. Several hundred children were treated in two phase II double-blind clinical trials, with marked improvement in sociability, parents insisting on a higher “presence” of their children. Using the same protocol, three independent studies show positive effects of treatment with bumetanide on the severity of autism. Our trials carried out by the Neurochlore company, created with Éric Lemonnier, Nouchine Hadjikhani and Denis Ravel, formed an essential basis for foreseeing the development of a treatment. And, indeed, with the agreement of the European authorities and the American Food and Drug Administration (FDA), and the collaboration of Neurochlore, the French pharmaceutical company Servier has started a phase III trial in Europe, Australia, Brazil and soon in the USA. The -hopefully near- future will tell if this approach is successful. Interestingly, brain imaging and gaze tracking work -done in collaboration with Nouchine Hadjikhani- showed improved visual communication and lower activation of the amygdala by treatment with bumetanide, confirming our working hypothesis. Thus, an idea based on fundamental research data confronted with clinical experience could lead to a medical treatment for autism, illustrating the importance of thinking outside the box. Understanding and treating autism involves studying pregnancy and birth [5]. It is necessary to determine how birth affects these maturation sequences and how to block the immature activities that these sequences generate. It is amazing that we know very little about how the brain is prepared for birth, which is a very stressful episode, or how this transition is altered in diseases of brain development. Clinically and therapeutically, we need to combine early diagnosis and behavioral treatment to alleviate the autism syndrome more effectively than later interventions. “Neuroarchaeology” provides a conceptual framework for approaching future research on the treatment of autism.
REFERENCES
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