TY - JOUR
T1 - Excitatory/inhibitory imbalance in autism
T2 - the role of glutamate and GABA gene-sets in symptoms and cortical brain structure
AU - Hollestein, Viola
AU - Poelmans, Geert
AU - Forde, Natalie J.
AU - Beckmann, Christian F.
AU - Ecker, Christine
AU - Mann, Caroline
AU - Schäfer, Tim
AU - Moessnang, Carolin
AU - Baumeister, Sarah
AU - Banaschewski, Tobias
AU - Bourgeron, Thomas
AU - Loth, Eva
AU - Dell’Acqua, Flavio
AU - Murphy, Declan G.M.
AU - Puts, Nicolaas A.
AU - Tillmann, Julian
AU - Charman, Tony
AU - Jones, Emily J.H.
AU - Mason, Luke
AU - Ambrosino, Sara
AU - Holt, Rosemary
AU - Bölte, Sven
AU - Buitelaar, Jan K.
AU - Naaijen, Jilly
N1 - Funding Information:
This work has been supported by the EU-AIMS (European Autism Interventions) and AIMS-2-TRIALS programmes which receive support from Innovative Medicines Initiative Joint Undertaking Grant No. 115300 and 777394, the resources of which are composed of financial contributions from the European Union’s FP7 and Horizon2020 Programmes, and from the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions, and AUTISM SPEAKS, Autistica and SFARI; by the Horizon2020 supported programme CANDY Grant No. 847818 and a Veni grant from the Netherlands organization for scientific research (NWO) under grant number VI.Veni.194.032 awarded to JN. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the authors and not necessarily those of the funders.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85146804176&partnerID=8YFLogxK
U2 - 10.1038/s41398-023-02317-5
DO - 10.1038/s41398-023-02317-5
M3 - Article
C2 - 36681677
AN - SCOPUS:85146804176
SN - 2158-3188
VL - 13
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 18
ER -