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Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism

Abstract

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behavior. To date, no pharmacological treatment has been approved that ameliorates social behavior in patients with ASD. Based on the excitation/inhibition imbalance theory of autism, we hypothesized that bromide ions, long used as an antiepileptic medication, could relieve core symptoms of ASD. We evaluated the effects of chronic sodium bromide (NaBr) administration on autistic-like symptoms in three genetic mouse models of autism: Oprm1−/−, Fmr1−/− and Shank3Δex13-16−/− mice. We showed that chronic NaBr treatment relieved autistic-like behaviors in these three models. In Oprm1−/− mice, these beneficial effects were superior to those of chronic bumetanide administration. At transcriptional level, chronic NaBr in Oprm1 null mice was associated with increased expression of genes coding for chloride ions transporters, GABAA receptor subunits, oxytocin and mGlu4 receptor. Lastly, we uncovered synergistic alleviating effects of chronic NaBr and a positive allosteric modulator (PAM) of mGlu4 receptor on autistic-like behavior in Oprm1−/− mice. We evidenced in heterologous cells that bromide ions behave as PAMs of mGlu4, providing a molecular mechanism for such synergy. Our data reveal the therapeutic potential of bromide ions, alone or in combination with a PAM of mGlu4 receptor, for the treatment of ASDs.

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Fig. 1: Chronic sodium bromide dose-dependently relieved social behavior deficits in Oprm1−/− mice, demonstrating superior effects to chronic bumetanide.
Fig. 2: Chronic sodium bromide administration relieved social behavior deficits, stereotypies and exacerbated anxiety in Fmr1−/− and Shank3∆ex13-16−/− mice.
Fig. 3: Chronic sodium bromide treatment induced transcriptional modifications in the reward/social circuit of Oprm1−/− mice.
Fig. 4: Sodium bromide and VU0155041, a positive allosteric modulator of mGlu4 receptors, show synergistic effects in Oprm1−/− mice.
Fig. 5: Bromide ions behave as PAMs of the mGlu4 receptor and shows synergistic effects with the mGlu4 PAM VU0155041.

Data availability

All data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank Dr. Thierry Plouvier for inspiring initial discussions on this project, Pr Frédérique Bonnet-Brilhault for critical reading of the manuscript, Yannick Corde for technical support, and Drs. Jorge Gandía and Sébastien Roux for assistance in performing behavioral experiments. We thank the Experimental Unit PAO-1297 (EU0028, Animal Physiology Experimental Facility, https://doi.org/10.15454/1.5573896321728955E12) from the INRAE-Val de Loire Centre for animal breeding and care.

Funding

We acknowledge the following funding sources: C-VaLo, Cisbio Bioassays, Perkin Elmer (IP1 FRET), European Regional Development Fund (ERDF), Inserm Transfert (CoPOC), Région Centre (ARD2020 Biomédicament – GPCRAb) and ERA-NET NEURON. This work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm), Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAe) and Université de Tours.

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Conceptualization: CD, JK, JPP, JLM, JAJB; Methodology: JK, JPP, JLM, JAJB; Investigation: CD, AL, AB, DJ, CT, JLM, JAJB; Visualization: CD, AB, CT, JLM, JAJB; Funding acquisition: JPP, JLM, JAJB; Project administration: JK, JPP, JLM, JAJB; Supervision: JK, JPP, JLM, JAJB; Writing: CD, JLM, JAJB.

Corresponding authors

Correspondence to Julie Le Merrer or Jerome A. J. Becker.

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Competing interests

JLM and JAJB are co-inventors of the patent WO2018096184: “Use of bromides in the treatment of autistic spectrum disorder”, US Patent App. 16/464,403, 2021 and patent application EP 21 194 699: “Methods for treating autism spectrum disorders”. CD, AL, AB, DJ, CT, JPP, and JK report no biomedical financial interests or potential conflicts of interest.

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Derieux, C., Léauté, A., Brugoux, A. et al. Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01317-1

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