Excitatory/inhibitory imbalance in autism: the role of glutamate and GABA gene-sets in symptoms and cortical brain structure

Viola Hollestein; Geert Poelmans; Natalie J. Forde; Christian F. Beckmann; Christine Ecker; Caroline Mann; Tim Schäfer; Carolin Moessnang; Sarah Baumeister; Tobias Banaschewski; Thomas Bourgeron; Eva Loth; Flavio Dell’Acqua; Declan G. M. Murphy; Nicolaas A. Puts; Julian Tillmann; Tony Charman; Emily J. H. Jones; Luke Mason; Sara Ambrosino; Rosemary Holt; Sven Bölte; Jan K. Buitelaar; Jilly Naaijen

doi:10.1038/s41398-023-02317-5

Translational Psychiatry (Jan 2023)

Excitatory/inhibitory imbalance in autism: the role of glutamate and GABA gene-sets in symptoms and cortical brain structure

Viola Hollestein,
Geert Poelmans,
Natalie J. Forde,
Christian F. Beckmann,
Christine Ecker,
Caroline Mann,
Tim Schäfer,
Carolin Moessnang,
Sarah Baumeister,
Tobias Banaschewski,
Thomas Bourgeron,
Eva Loth,
Flavio Dell’Acqua,
Declan G. M. Murphy,
Nicolaas A. Puts,
Julian Tillmann,
Tony Charman,
Emily J. H. Jones,
Luke Mason,
Sara Ambrosino,
Rosemary Holt,
Sven Bölte,
Jan K. Buitelaar,
Jilly Naaijen

Affiliations

Viola Hollestein: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
Geert Poelmans: Department of Human Genetics, Radboud University Medical Center
Natalie J. Forde: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
Christian F. Beckmann: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
Christine Ecker: Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
Caroline Mann: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University
Tim Schäfer: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe University
Carolin Moessnang: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg
Sarah Baumeister: Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
Tobias Banaschewski: Child and Adolescent Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg
Thomas Bourgeron: Institut Pasteur, Human Genetics and Cognitive Functions Unit
Eva Loth: Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
Flavio Dell’Acqua: Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
Declan G. M. Murphy: Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
Nicolaas A. Puts: Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
Julian Tillmann: Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann–La Roche Ltd.
Tony Charman: Department of Psychology, Institute of Psychiatry, Psychology, & Neuroscience, King’s College London
Emily J. H. Jones: Centre for Brain and Cognitive Development, Birkbeck, University of London, Henry Wellcome Building
Luke Mason: Centre for Brain and Cognitive Development, Birkbeck, University of London, Henry Wellcome Building
Sara Ambrosino: Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University
Rosemary Holt: Autism Research Centre, Department of Psychiatry, University of Cambridge
Sven Bölte: Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research; Department of Women’s and Children’s Health, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm
Jan K. Buitelaar: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
Jilly Naaijen: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center

DOI: https://doi.org/10.1038/s41398-023-02317-5
Journal volume & issue: Vol. 13, no. 1
pp. 1 – 9

Abstract

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Abstract The excitatory/inhibitory (E/I) imbalance hypothesis posits that imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism. However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood. We used innovative analysis methods—combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT) to investigate relationships between genetic variance, brain structure and autism symptomatology of participants from the AIMS-2-TRIALS LEAP cohort (autism = 359, male/female = 258/101; neurotypical control participants = 279, male/female = 178/101) aged 6–30 years. Using competitive gene-set analyses, we investigated whether aggregated genetic variation in glutamate and GABA gene-sets could be associated with behavioral measures of autism symptoms and brain structural variation. Further, using the same gene-sets, we corelated expression profiles throughout the cortex with differences in CT between autistic and neurotypical control participants, as well as in separate sensory subgroups. The glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group. In adolescents and adults, brain regions with greater gene-expression of glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants although in opposing directions. Additionally, the gene expression profiles were associated with CT profiles in separate sensory subgroups. Our results suggest complex relationships between E/I related genetics and autism symptom profiles as well as brain structure alterations, where there may be differential roles for glutamate and GABA.

Published in Translational Psychiatry

ISSN: 2158-3188 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: http://www.nature.com/tp/index.html

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