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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APA. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC; 2013.
Johnson CP, Myers SM. Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007;120:1183–215.
Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet 2014;383:896–910.
Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D, Keefer A, et al. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013;41:165–76.
Fombonne E, Green Snyder L, Daniels A, Feliciano P, Chung W, Consortium S. Psychiatric and medical profiles of autistic adults in the SPARK cohort. J Autism Dev Disord. 2020;50:3679–98.
Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S, An JY, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 2020;180:568–84 e23.
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012;485:237–41.
Park HR, Lee JM, Moon HE, Lee DS, Kim BN, Kim J, et al. A short review on the current understanding of autism spectrum disorders. Exp Neurobiol. 2016;25:1–13.
Lee E, Lee J, Kim E. Excitation/Inhibition imbalance in animal models of autism spectrum disorders. Biol Psychiatry. 2017;81:838–47.
Nelson SB, Valakh V. Excitatory/Inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 2015;87:684–98.
Rubenstein JL, Merzenich MM. Model of autism: Increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003;2:255–67.
Cellot G, Cherubini E. GABAergic signaling as therapeutic target for autism spectrum disorders. Front Pediatr. 2014;2:70.
Robertson CE, Ratai EM, Kanwisher N. Reduced GABAergic action in the autistic brain. Curr Biol: CB. 2016;26:80–5.
Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004;113:e472–86.
Jeste SS, Tuchman R. Autism spectrum disorder and epilepsy: Two sides of the same coin? J Child Neurol. 2015;30:1963–71.
Strasser L, Downes M, Kung J, Cross JH, De, Haan M. Prevalence and risk factors for autism spectrum disorder in epilepsy: A systematic review and meta-analysis. Dev Med Child Neurol. 2018;60:19–29.
O’Donnell C, Goncalves JT, Portera-Cailliau C, Sejnowski TJ. Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders. eLife. 2017;6:e26724.
Rinaldi T, Kulangara K, Antoniello K, Markram H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci USA. 2007;104:13501–6.
Shi R, Redman P, Ghose D, Hwang H, Liu Y, Ren X, et al. Shank proteins differentially regulate synaptic transmission. eNeurology. 2017;4:ENEURO.0163-15.2017.
Fung LK, Flores RE, Gu M, Sun KL, James D, Schuck RK, et al. Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder. Mol Psychiatry 2020;26:1634–46.
Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD. GABA(A) receptor downregulation in brains of subjects with autism. J Autism Dev Disord. 2009;39:223–30.
Oblak AL, Gibbs TT, Blatt GJ. Decreased GABA(B) receptors in the cingulate cortex and fusiform gyrus in autism. J Neurochem. 2010;114:1414–23.
Sesarini CV, Costa L, Granana N, Coto MG, Pallia RC, Argibay PF. Association between GABA(A) receptor subunit polymorphisms and autism spectrum disorder (ASD). Psychiatry Res. 2015;229:580–2.
Mahdavi M, Kheirollahi M, Riahi R, Khorvash F, Khorrami M, Mirsafaie M. Meta-analysis of the association between GABA receptor polymorphisms and Autism Spectrum Disorder (ASD). J Mol Neurosci: MN. 2018;65:1–9.
Adusei DC, Pacey LK, Chen D, Hampson DR. Early developmental alterations in GABAergic protein expression in fragile X knockout mice. Neuropharmacology 2010;59:167–71.
Banerjee A, Garcia-Oscos F, Roychowdhury S, Galindo LC, Hall S, Kilgard MP, et al. Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism. Int J Neuropsychopharmacol. 2013;16:1309–18.
Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 2010;468:263–9.
Curia G, Papouin T, Seguela P, Avoli M. Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. Cereb Cortex. 2009;19:1515–20.
Han S, Tai C, Jones CJ, Scheuer T, Catterall WA. Enhancement of inhibitory neurotransmission by GABAA receptors having alpha2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 2014;81:1282–89.
Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist 2012;18:467–86.
Eftekhari S, Mehvari Habibabadi J, Najafi Ziarani M, Hashemi Fesharaki SS, Gharakhani M, Mostafavi H, et al. Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy. Epilepsia 2013;54:e9–12.
Soul JS, Bergin AM, Stopp C, Hayes B, Singh A, Fortuno CR, et al. A pilot randomized, controlled, double-blind trial of bumetanide to treat neonatal seizures. Ann Neurol. 2020;89:327–40.
Tyzio R, Nardou R, Ferrari DC, Tsintsadze T, Shahrokhi A, Eftekhari S, et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 2014;343:675–9.
Lemonnier E, Degrez C, Phelep M, Tyzio R, Josse F, Grandgeorge M, et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry. 2012;2:e202.
Fernell E, Gustafsson P, Gillberg C. Bumetanide for autism: Open-label trial in six children. Acta Paediatrica. 2020;110:1548–53.
Pearce JM. Bromide, the first effective antiepileptic agent. J Neurol, Neurosurg, Psychiatry. 2002;72:412.
Uhr L, Pollard JC, Miller JG. Behavioral effects of chronic administration of psychoactive drugs to anxious patients. Psychopharmacologia 1959;1:150–68.
Almeida AC, Scorza FA, Rodrigues AM, Arida RM, Carlesso FN, Batista AG, et al. Combined effect of bumetanide, bromide, and GABAergic agonists: an alternative treatment for intractable seizures. Epilepsy Behav. 2011;20:147–9.
Woody RC. Bromide therapy for pediatric seizure disorder intractable to other antiepileptic drugs. J Child Neurol. 1990;5:65–7.
Suzuki S, Kawakami K, Nakamura F, Nishimura S, Yagi K, Seino M. Bromide, in the therapeutic concentration, enhances GABA-activated currents in cultured neurons of rat cerebral cortex. Epilepsy Res. 1994;19:89–97.
Gagnon KB, Adragna NC, Fyffe RE, Lauf PK. Characterization of glial cell K-Cl cotransport. Cell Physiol Biochem: Int J Exp Cell Physiol, Biochem, Pharmacol. 2007;20:121–30.
Kinne R, Kinne-Saffran E, Scholermann B, Schutz H. The anion specificity of the sodium-potassium-chloride cotransporter in rabbit kidney outer medulla: studies on medullary plasma membranes. Pflug Arch: Eur J Physiol. 1986;407(Suppl 2):S168–73.
Becker JA, Clesse D, Spiegelhalter C, Schwab Y, Le Merrer J, Kieffer BL. Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology 2014;39:2049–60.
Jamot L, Matthes HW, Simonin F, Kieffer BL, Roder JC. Differential involvement of the mu and kappa opioid receptors in spatial learning. Genes Brain Behav. 2003;2:80–92.
Jung KM, Sepers M, Henstridge CM, Lassalle O, Neuhofer D, Martin H, et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun. 2012;3:1080.
Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 2012;74:49–56.
Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 2011;472:437–42.
Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 1996;383:819–23.
Mientjes EJ, Nieuwenhuizen I, Kirkpatrick L, Zu T, Hoogeveen-Westerveld M, Severijnen L, et al. The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo. Neurobiol Dis. 2006;21:549–55.
Pujol CN, Pellissier LP, Clément C, Becker JAJ, Le Merrer J. Back-translating behavioral intervention for autism spectrum disorders to mice with blunted reward restores social abilities. Transl Psychiatry. 2018;8:197.
Holmes GL, Tian C, Hernan AE, Flynn S, Camp D, Barry J. Alterations in sociability and functional brain connectivity caused by early-life seizures are prevented by bumetanide. Neurobiol Dis. 2015;77:204–19.
Becker JAJ, Pellissier LP, Corde Y, Laboute T, Leaute A, Gandia J, et al. Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure in male mice. Neuropsychopharmacology 2021;46:1373–85.
Tora AS, Rovira X, Dione I, Bertrand HO, Brabet I, De Koninck Y, et al. Allosteric modulation of metabotropic glutamate receptors by chloride ions. Faseb J. 2015;29:4174–88.
Kuang D, Hampson DR. Ion dependence of ligand binding to metabotropic glutamate receptors. Biochem Biophys Res Commun. 2006;345:1–6.
Conklin BR, Farfel Z, Lustig KD, Julius D, Bourne HR. Substitution of three amino acids switches receptor specificity of Gq alpha to that of Gi alpha. Nature 1993;363:274–6.
Goldstein DB. Sodium bromide and sodium valproate: effective suppressants of ethanol withdrawal reactions in mice. J Pharm Exp Ther. 1979;208:223–7.
Hayashi K, Ueshima S, Ouchida M, Mashimo T, Nishiki T, Sendo T, et al. Therapy for hyperthermia-induced seizures in Scn1a mutant rats. Epilepsia 2011;52:1010–7.
Charalambous M, Shivapour SK, Brodbelt DC, Volk HA. Antiepileptic drugs’ tolerability and safety-a systematic review and meta-analysis of adverse effects in dogs. BMC Vet Res. 2016;12:79.
Trepanier LA, Babish JG. Pharmacokinetic properties of bromide in dogs after the intravenous and oral administration of single doses. Res Vet Sci. 1995;58:248–51.
Steinhoff BJ, Kruse R. Bromide treatment of pharmaco-resistant epilepsies with generalized tonic-clonic seizures: a clinical study. Brain Dev. 1992;14:144–9.
Vidaurre J, Gedela S, Yarosz S. Antiepileptic drugs and liver disease. Pediatr Neurol. 2017;77:23–36.
Pavelka S, Babicky A, Vobecky M, Lener J, Svandova E. Bromide kinetics and distribution in the rat. I. Biokinetics of 82Br-bromide. Biol trace Elem Res. 2000;76:57–66.
Rauws AG. Pharmacokinetics of bromide ion-an overview. Food Chem Toxicol: Int J published Br Ind Biol Res Assoc. 1983;21:379–82.
Vaiseman N, Koren G, Pencharz P. Pharmacokinetics of oral and intravenous bromide in normal volunteers. J Toxicol Clin Toxicol. 1986;24:403–13.
Sprengers JJ, van Andel DM, Zuithoff NPA, Keijzer-Veen MG, Schulp AJA, Scheepers FE, et al. Bumetanide for Core Symptoms of Autism Spectrum Disorder (BAMBI): A single center, double-blinded, participant-randomized, placebo-controlled, Phase-2 superiority trial. J Am Acad Child Adolesc Psychiatry. 2020;S0890-8567:31290–9.
Hays SA, Huber KM, Gibson JR. Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry. J Neurosci. 2011;31:14223–34.
Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27:370–7.
Yoo T, Cho H, Lee J, Park H, Yoo YE, Yang E, et al. GABA neuronal deletion of Shank3 Exons 14-16 in mice suppresses striatal excitatory synaptic input and induces social and locomotor abnormalities. Front Cell Neurosci. 2018;12:341.
Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, et al. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism. 2010;1:15.
Yang M, Bozdagi O, Scattoni ML, Wohr M, Roullet FI, Katz AM, et al. Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J Neurosci. 2012;32:6525–41.
Jaramillo TC, Speed HE, Xuan Z, Reimers JM, Escamilla CO, Weaver TP, et al. Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function. Autism Res. 2017;10:42–65.
Paluszkiewicz SM, Martin BS, Huntsman MM. Fragile X syndrome: The GABAergic system and circuit dysfunction. Dev Neurosci. 2011;33:349–64.
Van der Aa N, Kooy RF. GABAergic abnormalities in the fragile X syndrome. Eur J Paediatr Neurol. 2020;24:100–04.
Centonze D, Rossi S, Mercaldo V, Napoli I, Ciotti MT, De Chiara V, et al. Abnormal striatal GABA transmission in the mouse model for the fragile X syndrome. Biol Psychiatry. 2008;63:963–73.
Wang W, Li C, Chen Q, van der Goes MS, Hawrot J, Yao AY, et al. Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism. J Clin Invest. 2017;127:1978–90.
Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, et al. Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol. 2008;74:1345–58.
Sala-Rabanal M, Yurtsever Z, Nichols CG, Brett TJ. Secreted CLCA1 modulates TMEM16A to activate Ca(2+)-dependent chloride currents in human cells. eLife 2015;4:e05875.
Seo KH, Jin Y, Jung SY, Lee SH. Comprehensive behavioral analyses of anoctamin1/TMEM16A-conditional knockout mice. Life Sci. 2018;207:323–31.
Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Z, et al. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc Natl Acad Sci USA. 2016;113:751–6.
Doyon N, Vinay L, Prescott SA, De, Koninck Y. Chloride regulation: A dynamic equilibrium crucial for synaptic inhibition. Neuron. 2016;89:1157–72.
Meierkord H, Grunig F, Gutschmidt U, Gutierrez R, Pfeiffer M, Draguhn A, et al. Sodium bromide: Effects on different patterns of epileptiform activity, extracellular pH changes and GABAergic inhibition. Naunyn-Schmiedeberg’s Arch Pharmacol. 2000;361:25–32.
Dolen G, Darvishzadeh A, Huang KW, Malenka RC. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 2013;501:179–84.
Gigliucci V, Leonzino M, Busnelli M, Luchetti A, Palladino VS, D’Amato FR, et al. Region specific up-regulation of oxytocin receptors in the opioid oprm1 (−/−) mouse model of autism. Front Pediatr. 2014;2:91.
Dunn HA, Zucca S, Dao M, Orlandi C, Martemyanov KA. ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior. Mol Psychiatry. 2019;24:1902–19.
Argyropoulos A, Gilby KL, Hill-Yardin EL. Studying autism in rodent models: Reconciling endophenotypes with comorbidities. Front Hum Neurosci. 2013;7:417.
Silverman JL, Yang M, Lord C, Crawley JN. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci. 2010;11:490–502.
Hadders-Algra M. Early diagnostics and early intervention in neurodevelopmental disorders-age-dependent challenges and opportunities. J Clin Med. 2021;10:861.
Smith T, Klorman R, Mruzek DW. Predicting outcome of community-based early intensive behavioral intervention for children with autism. J Abnorm Child Psychol. 2015;43:1271–82.
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.
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.
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. 47, 1680–1692 (2022). https://doi.org/10.1038/s41386-022-01317-1