The developing brain is not a small adult brain. Neurons follow developmental sequences with a progressive modification of their electrical properties. Immature cells present ionic currents and patterns that are unique to them and help validating the formation of brain networks, enabling cells to fire and connect together. I have suggested that an insult, whether genetic or environmental, deviates developmental sequences leading to neurons that remain “immature” in the adult brain, presenting immature patterns and aberrant connections and leading to neurodevelopmental disorders.
Based on this concept, called the Neuroarcheology concept, I propose that these immature ensembles are the cause of the disorder. Now, it is widely accepted that Autism Spectrum Disorders (ASD) are “born” in utero and therefore, according to this hypothesis, neurons might keep immature features. We confirmed this in animal models relying on the universal development of intracellular concentrations of chloride ([Cl-]i) and GABA actions.
Indeed, we discovered 3 decades ago a developmental shift from neurons with high [Cl-]i and excitatory actions of GABA to low [Cl-]i and inhibitory GABA actions. We hypothesized that in ASD neurons have high [Cl-]i as if they have remained immature, and we’ve shown that this was the case in rodent models of drug-induced-ASD, Fragile-X and Rett syndromes, and Maternal Immune Activation.
Also, we demonstrated that restoring low [Cl-]i and GABAergic inhibition with an antagonist of the main chloride importer (Bumetanide) attenuates autism severity. Relying on these observations, we have performed two phase II clinical trials showing that Bumetanide attenuates the severity of autism in children and adolescents.
In parallel studies and to further evaluate the role of the Neuroarcheology concept in ASD, we have recently shown that neurons grow during parturition and birth in autistic rats but not in age-matched naïve ones, indicating a perturbation of the in utero developmental process by the pathogenic inaugurating event.
The identification of persistent immature features will enable to develop novel treatments using agents that selectively silence these neuronal ensembles, performing a sort of pharmaceutical surgery. This approach will not “cure” ASD but will significantly attenuate it.
ABOUT THE SPEAKER:
After a PhD dedicated to mechanisms of memory processes, and 2 postdoctoral fellowships dedicated to epilepsies, I was nominated head of a French Medical Research council Unit (INSERM) in Paris in the largest maternity hospital (1986).
Dedicating my work on recording immature neurons, my colleagues and I discovered fundamental features including the GABA/Chloride shift and early immature patterns. I then moved to Marseille to create and direct the Mediterranean Institute of Neurobiology (INMED) animating studies directed on how the brain prepares for birth.
My current basic research work performed in the Neurochlore company is centered on maternity and birth in relation to brain disorders and based on the Neuroarcheology concept. This concept calls for a new way of studying and treating developmental disorders hoping to attenuate its severity by blocking the immature features of neurons that have been impacted by the inaugurating in utero insult.
This talk was part of Synchrony 2020 Online Symposium - 'From Bench to Biopharma', organised by the The BRAIN Foundation in partnership with UC Davis MIND Institute and CalTech.
For more Synchrony 2020 talks and highlights: [ Ссылка ]
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Synchrony [ Ссылка ] is the first and only international symposium on translational research in #autism, that brings together academia, #biotech, pharmaceutical companies and #venture partners from around the world with the mission to improve health and quality of life of people with #autismspectrumdisorder.
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The BRAIN Foundation [ Ссылка ] is a 501c(3) non-profit. The founders of BRAIN envision a world where every child and adult on the autism spectrum is healthy, participates fully in education and employment, and has a better quality of life. It aims to catalyze research that results in evidence-based interventions for the disabilities associated with autism, and also results in better medical standard of care.
To accomplish this, it funds impactful research through #philanthropy and our network of partners in the venture, corporate, and grassroots community.
