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Glutamatergic synapse in autism: a complex story for a complex disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

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Fig. 1: Quantification of the brain Glu and Glx levels and Glu sub-metabolomes in the serum and urines in individuals with ASD and controls.
Fig. 2: Translational brain imaging of mGluR5 using [18F]FPEB brain in adults with ASD and in an animal model of ASD compared to controls.

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Acknowledgements

The clinical study was supported by the French National Agency for Research (“Investissements d’Avenir” no. ANR-11-LABX-0018-01), IRON. This study was funded in part by the “Région centre Val de Loire APR-IA 2014-850”. We thank the staffs at the CERRP, iBrain, CIC 1415, PST-ASB core facility and the staff of the child psychiatry unit and the nuclear medicine department of the university hospital of Tours. We also thank the PRIMEX core facility from the Angers University for the MR-experiments to build the MRI template for male rats at early-adolescence. We thank Jacques Dupont for its technical assistance on preclinical behavioral experiments. We extend our deep gratitude to the participants of this study.

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Conceptualization: FBB, FL, LG, MJSR, PE, and SC; Data acquisition: AL, CB, CR, EHD, FBB, JV, LB, LG, MJSR, SC, SR, and VG; Data analysis: ACD, CT, LB, LG, LN, FB, FBB, MG, MJSR, NA, PE, and SM; Manuscript writing: FB, FBB, LG, MJSR, NA, and PE.

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Correspondence to Frédérique Bonnet-Brilhault.

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Galineau, L., Arlicot, N., Dupont, AC. et al. Glutamatergic synapse in autism: a complex story for a complex disorder. Mol Psychiatry 28, 801–809 (2023). https://doi.org/10.1038/s41380-022-01860-9

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