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Yehezkel Ben-Ari

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Yehezkel Ben-Ari
Born (1943-12-01) 1 December 1943 (age 81)
Cairo, Egypt
Alma materHebrew University Jerusalem, Paris Sorbonne University
Known forWork on neurogenesis and neurological pathologies
AwardsGrand Prix de l'INSERM (2009)
Scientific career
FieldsNeuroscience
InstitutionsInstitut de neurobiologie de la Méditerranée de l'INSERM
Neurochlore
B&A Therapeutics
B&A Biomedical
B&A Oncomedical

Yehezkel Ben-Ari (born 1 December 1943) is a neurobiologist specializing in brain development and the development of brain disorders. He has made seminal contributions to the understanding of brain activity in health and disease and notably autism, epilepsies and related infantile disorders.

Biography

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Yehezkel Ben-Ari began his academic career at the Hebrew University of Jerusalem in Israel, where he completed his Bachelor's and Master's degrees. In 1966, he pursued advanced studies at the Sorbonne Université in France where he obtained his DEA. In 1971, he completed his PhD with a focus on neuronal plasticity.[1][2]

From 1973 to 1980, Ben-Ari undertook several post-doctoral fellowships at prestigious institutions, including Cambridge University, Oslo University, and Mc Gill University in Montreal. Upon his return to France, he was engaged by the Centre National de la Recherche Scientifique (CNRS), where he initially headed a team studying epilepsy at the Alfred Fessart Laboratory of Nervous Physiology.[1][2]

In 1986, Ben-Ari was appointed as the head of the INSERM U29 unit, "Neurobiology and Pathophysiology of Development," succeeding Professor Alexandre Minkowski. This unit was situated within the Port Royal maternity hospital in Paris. Ben-Ari later moved his entire team to Marseille in 1999, where he established and led the Institut de Neurobiologie de la Méditerranée (INMED) of INSERM, located on the scientific campus of Luminy.[1][2]

In 2008, after retiring from his leadership role, Ben-Ari shifted his focus towards the creation of several start-up companies. Collaborating with renowned figures like Eric Lemonier, Nouchine Hadjikhani, Constance Hammond, Philippe Damier, and Francois Berger, these start-ups aim to understand and develop treatments for various brain disorders, including Autism Spectrum Disorders, Parkinson's Disease, and brain tumors.[3]

Scientific achievements

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Yehezkel Ben-Ari studied in His PhD work neuronal plasticity, recording in vivo neurons in the amygdala and determining with a variety of mathematical tools the modifications of neuronal activity during a classical sensory-sensory random Pavlovian type conditioning. His main discovery was that during conditioning the so called ongoing or spontaneous activity is also modified leading to alterations that precedes the conditional stimulus as if the neuron expected the stimulus to come.[1]

His Post doc in University of Cambridge  at the MRC unit of neurochemistry directed by Prof L Iversen was centered on the amygdala where he determined with R Zigmond the levels of Gabaergic and cholinergic markers in substructures of the complex.[4]

In parallel, he recorded with I Kanazawa  and JS Kelly neuron in the amygdala in vivo  reporting for the first time their activity and responses to a variety of neuroleptics. Yehezkel Ben-Ari also reported -with Kanazawa and Kelly-  in Nature the striking effects of  acetylcholine on neurons of the reticularis nucleus – a major structure that controls sensory inputs to the cortex.[5]

Returning to France, Yehezkel Ben-Ari formed a team to study epilepsies in Temporal Lobe Epilepsies (TLE) -a pharmaco-resistant type of epilepsies. Studying the action of kainic acid -an epileptogenic agent present in algae – he discovered the animal model of TLE produced by kainic acid that mimicked the main features of TLE including the pattern of damage, the resistance to treatments, and the mechanisms underlying how “seizures beget seizures “ due to the  formation by propagated seizures of distant  seizures foci.[6] The pathogenic reactive form of plasticity generates aberrant synapses that generate more seizures. This general scheme is now considered as a major cause of reactive epilepsies.[7] The review paper published on this domain is the 3rd most quoted paper in the field of epilepsies.[8]

In 1986, Yehezkel Ben-Ari was nominated head of the Unit 29 of INSERM located within Hôpital Cochin-Port-Royal. He started to investigate the properties of immature neurons in rodent brain slices, making the first recording from in utero rodent and later non-human primate brains. These studies led to fundamental evolutionary conserved rules notably the high intracellular level of chloride (CL-)i of immature neurons associated with paradoxical excitatory actions of the adult classical inhibitory transmitter GABA, exciting immature neurons and inhibiting adult ones. This underlies the trophic role of GABA that stimulates neuronal growth, synapse and network formation. Yehezkel Ben-Ari then spent the next decades investigating the roles, mechanisms of the developmental GABA shift -that was validated in all animal species from worms to humans- and its clinical implications.[9]

Moving in 1999 to Marseille to the construct INMED – an institute dedicated then to study brain development- he led teams working in this domain showing notably that the GABA shift is reversed in pathological conditions including epilepsies, Autism Spectrum Disorders and other disorders: GABA “again“excites neurons with high chloride level due to enhanced activity of the main chloride importer NKCC1 and reduced activity of the main chloride exporter KCC2. He also discovered that parturition and birth are associated with an abrupt transient reduction of chloride (and polarity of GABA actions) due to the hormone oxytocin that triggers delivery. He then showed that in autism, this shift does not take place -GABA remains excitatory during a highly vulnerable period. These studies led to a flurry of investigations on parturition and birth and the roles of Oxytocin and the impact of these alterations in the pathogenesis of brain disorders.

In 2008, retiring from academic research, Yehezkel Ben-Ari shifted to create startups dedicated to understand and treat brain disorders. He proposed a fundamental concept called the “neuroarcheology concept” according to which in utero insults deviate developmental sequences leading to neurons endowed with immature features that are the final cause of disorders. Therefore, drugs aimed at selectively blocking immature properties -such as high chloride levels and excitatory actions of GABA- are highly suited to pharmaceutically silencing the perturbing neurons.[10]

This hypothesis was first tested in Autism Spectrum Disorders (ASD) by Neurochlore,[11] a startup dedicated to treat ASD. In animal models of ASD, the chloride importer antagonist that reduces (CL-)i levels -Bumetanide –restores inhibitory actions of GABA and attenuates behavioral alterations in animal models. With Dr Eric Lemonnier – a psychiatrist treating children with ASD- they performed pilot trials[12] and phase 2A and 2B trials[13]  to treat children (3-11 and later 2-18 years old). The differences treated/placebo were statistically significant and the clinical observations were highly positive with an amelioration of social interactions and reduction of agitation. These results were validated in many trials made in China, England, Sweden and Holland with several hundreds of children treated successfully.[14][15][16][17]

In 2021, a final phase 3 was then made (210 children 2-6 and 210 children 7-18yrs old recruited in 40 centers in Europe, Brazil, Australia and US). The results were negative with no difference between placebo and treated children.[18] However, bumetanide responders can be identified in large trials using EEG measures or inflammatory signals suggesting that the treatment is efficient in subpopulations of patients.[19] If bumetanide is indeed efficient in a subpopulation of children it is essential to identify this population to enhance success of future trials and attenuate the severity of clinical signs in a disorder that is orphan of treatments.[20]  

Maternity and ASD

Experimental and human investigations indicate that ASD is born in utero. Relying on this, Yehezkel Ben-Ari and his team in BA-biomedical analyzed all maternity data available in French Maternities (roughly 200 parameters) in children with ASD and neurotypical ones in Limoges. The program enabled to identify almost all babies who will not be diagnosed with ASD years later and roughly half those who will be. Interestingly, impacting parameters included expected ones -sex, viral infections etc.- and unexpected ones- earlier upside-down head rotation, femur size 2nd trimester etc. The Cephalic Perimeter (CP) was bigger shortly before birth in future babies with than without ASD. in rodents, the team showed that brain structures and neurons increase size/volumes during parturition and birth in ASD not in naïve rodents. Therefore, major events occurring during in utero growth, parturition and birth are impacted by in ASD.[21][22]

Publications

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Ben-Ari has published over 500 publications in leading scientific journals.[23]

He is amongst the 5 most quoted French Neuroscientists.[24]

Awards and honours

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Inmed

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Ben-Ari is the founder and the first director of the Institute of Neurobiology of the Mediterranean sea (INMED) inaugurated in 2004. The Building was constructed by a highly appraised architect – the Norvegian Snøhetta- who also constructed the library of Alexandria in Egypt and the opera of Oslo amongst many outstanding institutions. INMED is initially based on the migration of virtually all researchers and technicians from paris (INSERM UNIT 29). In addition to experimental groups and facilities, INMED include a collection of art work collected by Yehezkel Ben-Ari during several decades and a special teaching ensemble devoted to lyceum classes preferentially coming from poor neighborhood.  

References

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  1. ^ a b c d "Yehezkel Ben-Ari ⋅ Inserm, La science pour la santé". INSERM (in French). Retrieved 2023-06-20.
  2. ^ a b c "Biography & Research". Ben-Ari's Blog. Retrieved 2023-06-20.
  3. ^ Gardet-Pizzo, Maëva (2018-12-21). "Yehezkel Ben-Ari, la science comme un art". La Tribune (in French). Retrieved 2023-06-20.
  4. ^ Ben-Ari, Y.; Kanazawa, I.; Zigmond, R. E. (1976-06-01). "Regional distribution of glutamate decarboxylase and gaba within the amygdaloid complex and stria terminalis system of the rat". Journal of Neurochemistry. 26 (6): 1279–1283. doi:10.1111/j.1471-4159.1976.tb07019.x. ISSN 0022-3042. PMID 932733. S2CID 32751839.
  5. ^ Ben-Ari, Y.; Kanazawa, I.; Kelly, J. S. (1976-01-29). "Exclusively inhibitory action of iontophoretic acetylcholine on single neurones of feline thalamus". Nature. 259 (5541): 327–330. Bibcode:1976Natur.259..327B. doi:10.1038/259327a0. ISSN 1476-4687. PMID 1250368. S2CID 4188053.
  6. ^ Ben-Ari, Yehezkel; Crepel, Valerie; Represa, Alfonso (2008-05-08). "Seizures Beget Seizures in Temporal Lobe Epilepsies: The Boomerang Effects of Newly Formed Aberrant Kainatergic Synapses". Epilepsy Currents. 8 (3): 68–72. doi:10.1111/j.1535-7511.2008.00241.x. ISSN 1535-7597. PMC 2384153. PMID 18488058.
  7. ^ Ben-Ari, Y. (1985-02-01). "Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy". Neuroscience. 14 (2): 375–403. doi:10.1016/0306-4522(85)90299-4. ISSN 0306-4522. PMID 2859548. S2CID 33597110.
  8. ^ Ibrahim, George M.; Carter Snead, O. (2012-03-29). "The most cited works in epilepsy: Trends in the "Citation Classics"". Epilepsia. 53 (5): 765–770. doi:10.1111/j.1528-1167.2012.03455.x. PMID 22462799. S2CID 24128231.
  9. ^ Ben-Ari, Yehezkel (2002-09-01). "Excitatory actions of gaba during development: the nature of the nurture". Nature Reviews Neuroscience. 3 (9): 728–739. doi:10.1038/nrn920. ISSN 1471-0048. PMID 12209121. S2CID 8116740.
  10. ^ Ben-Ari, Yehezkel (2008-10-27). "Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders". Trends in Neurosciences. 31 (12): 626–636. doi:10.1016/j.tins.2008.09.002. PMID 18951639. S2CID 8089019.
  11. ^ "Research on Neurodevelopmental Disorders". Neurochlore. Retrieved 2023-06-20.
  12. ^ Lemonnier, Eric; Ben-Ari, Yehezkel (December 2010). "The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects: Bumetanide in autism". Acta Paediatrica. 99 (12): 1885–1888. doi:10.1111/j.1651-2227.2010.01933.x. PMID 20608900. S2CID 10539650.
  13. ^ Lemonnier, E.; Degrez, C.; Phelep, M.; Tyzio, R.; Josse, F.; Grandgeorge, M.; Hadjikhani, N.; Ben-Ari, Y. (December 2012). "A randomised controlled trial of bumetanide in the treatment of autism in children". Translational Psychiatry. 2 (12): e202. doi:10.1038/tp.2012.124. ISSN 2158-3188. PMC 3565189. PMID 23233021.
  14. ^ Kharod, Shivani C.; Kang, Seok Kyu; Kadam, Shilpa D. (2019-04-24). "Off-Label Use of Bumetanide for Brain Disorders: An Overview". Frontiers in Neuroscience. 13: 310. doi:10.3389/fnins.2019.00310. ISSN 1662-453X. PMC 6491514. PMID 31068771.
  15. ^ Savardi, Annalisa; Borgogno, Marco; De Vivo, Marco; Cancedda, Laura (2021-10-14). "Pharmacological tools to target NKCC1 in brain disorders". Trends in Pharmacological Sciences. 42 (12): 1009–1034. doi:10.1016/j.tips.2021.09.005. PMID 34620512. S2CID 238475807.
  16. ^ Ben-Ari, Yehezkel (2017-08-17). "NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders". Trends in Neurosciences. 40 (9): 536–554. doi:10.1016/j.tins.2017.07.001. PMID 28818303. S2CID 3597037.
  17. ^ Ben-Ari, Y. (2014-10-24). "The GABA excitatory/inhibitory developmental sequence: A personal journey". Neuroscience. 279: 187–219. doi:10.1016/j.neuroscience.2014.08.001. PMID 25168736. S2CID 11436955.
  18. ^ Apothéloz, Christian (2021-09-20). "Autisme : Neurochlore reconnaît l'échec du traitement par la Bumétanide". Gomet' Santé (in French).
  19. ^ Juarez-Martinez, Erika L.; Sprengers, Jan J.; Cristian, Gianina; Oranje, Bob; van Andel, Dorinde M.; Avramiea, Arthur-Ervin; Simpraga, Sonja; Houtman, Simon J.; Hardstone, Richard; Gerver, Cathalijn; Jan van der Wilt, Gert; Mansvelder, Huibert D.; Eijkemans, Marinus J.C.; Linkenkaer-Hansen, Klaus; Bruining, Hilgo (2023-03-06). "Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder". Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 8 (3): 251–261. doi:10.1016/j.bpsc.2021.08.009. PMID 34506972. S2CID 237480678.
  20. ^ Lemonnier, Eric; Robin, Gaëlle; Degrez, Céline; Tyzio, Roman; Grandgeorge, Marine; Ben-Ari, Yehezkel (June 2013). "Treating Fragile X syndrome with the diuretic bumetanide: a case report". Acta Paediatrica. 102 (6): e288–e290. doi:10.1111/apa.12235. PMID 23647528. S2CID 207036693.
  21. ^ Caly, Hugues; Rabiei, Hamed; Coste-Mazeau, Perrine; Hantz, Sebastien; Alain, Sophie; Eyraud, Jean-Luc; Chianea, Thierry; Caly, Catherine; Makowski, David; Hadjikhani, Nouchine; Lemonnier, Eric; Ben-Ari, Yehezkel (2021-03-25). "Machine learning analysis of pregnancy data enables early identification of a subpopulation of newborns with ASD". Scientific Reports. 11 (1): 6877. Bibcode:2021NatSR..11.6877C. doi:10.1038/s41598-021-86320-0. ISSN 2045-2322. PMC 7994821. PMID 33767300.
  22. ^ Ben-Ari, Yehezkel; Caly, Hugues; Rabiei, Hamed; Lemonnier, Éric (2022-05-01). "Pronostiquer tôt les troubles du spectre autistique : Un défi ?". Médecine/Sciences (in French). 38 (5): 431–437. doi:10.1051/medsci/2022054. ISSN 0767-0974. PMID 35608465. S2CID 249051471.
  23. ^ "Yehezkel Ben-Ari". scholar.google.com. Retrieved 2023-06-20.
  24. ^ "Yehezkel Ben-Ari: H-index & Awards - Academic Profile". Research.com.
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