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Understanding and treating autism: a dual approach based on the Neuroarcheology concept

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The developing brain is not a small adult brain: all ionic currents and patterns are unique to immature cells. Neurons follow developmental sequences with a progressive modification of their electrical properties. Immature patterns help validating the formation of brain networks, enabling cells to fire and connect together. I have suggested the neuroarcheology concept according to which that an insult -whether genetic or environmental – deviates these sequences leading to neurons that remain “immature” in the adult brain, with immature patterns and aberrant connections. These immature ensembles are the cause of the disorder 1! As Autism is “born” in utero, it might be amenable to treatment relying on this concept. We have adopted a dual approach i) an early prognosis of autism relying on maternity data (caly et al Sci.Rep. 2021). We developed a Machine Learning program that can analyze without any a priori large number of parameters – in France almost 120 per each maternity- and analyze them to provide a prognosis and to identify parameters that impact the decision (ASD or Neurotypic). Using this “Genesis ML” program, we report that it is possible to identify almost 100% of babies that will not have an ASD diagnosis and a subpopulation of babies who will but with a precision of 75%. Large trials in many French maternities, European and possibly US ones are now planned. If validated, Genesis ML will provide a novel important avenue to enable early identification of babies at risk of ASD . enable an early identification of babies at risk and use psycho-educative known to be more efficient when used early. ii) We discovered 3 decades ago a shift from neurons with High (Cl-)i levels and excitatory actions of GABA to low levels and inhibitory GABA actions 2,3. Now, in autism, many neurons have high (Cl-)i levels as if they have remained immature. This is the case in drug induced ASD , Fragile X, Rett syndrome and Maternal Immune Activation 4,5,6. Restoring low (Cl-)i levels & GAB Aergic inhibition with an antagonist of the main chloride importer Bumetanide attenuates autism severity. iii) Relying on these observations, we have performed 2 phase 2 including a pivotal phase 2B trial showing that bumetanide attenuates the severity of autism7,8. These results have been confirmed by 7 independent pilot or double blind randomized trials. Eye tracking and brain imaging studies showed an amelioration of the communication and reduction of the activation of the amygdala. With the French pharmaceutic company Servier, we are now performing the final FDA /EMA approved phase 3 in Europe, USA , Brazil and Australia (400 children -2-18 years old), final results are expected september 2021 and if positive a treatment in the market early 2024. Therefore our approach from bench to bed has indeed shown that it might be possible to establish a prognosis at birth and using selective antagonists of immature neurons to attenuate the severity of autism. Clearly to understand and treat autism, it is essential to determine the alterations occurring in utero that announce autism. References: 1. Ben-Ari, Y. Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders. Trends in Neurosciences (2008) doi:10.1016/j.tins.2008.09.002. 2. Cherubini, E., Gaiarsa, J. L. J. L. & Ben-Ari, Y. GABA : an excitatory transmitter in early postnatal life. Trends Neurosci. 14, 515–519 (1991). 3. Ben-Ari, Y. Excitatory actions of GABA during development: The nature of the nurture. Nat. Rev. Neurosci. 3, 728–739 (2002). 4. Ben-Ari, Y. The GABA excitatory/inhibitory developmental sequence: A personal journey. Neuroscience 279, 187–219 (2014). 5. Fernandez, A. et al. The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth. Cereb. Cortex 29, (2019). 6. Tyzio, R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science (80-. ). 343, 675–679 (2014). 7. Lemonnier, E. et al. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl. Psychiatry (2017) doi:10.1038/tp.2017.10. 8. Lemonnier, E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Translational Psychiatry (2012).

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