Excitatory/inhibitory imbalance in autism: the role of glutamate and GABA gene-sets in symptoms and cortical brain structure.
Viola HollesteinGeert PoelmansNatalie J FordeChristian F BeckmannChristine EckerCaroline MannTim SchäferCarolin MoessnangSarah BaumeisterTobias BanaschewskiThomas BourgeronEva LothFlavio Dell'AcquaDeclan G M MurphyNicolaas A J PutsJulian TillmannTony CharmanEmily J H JonesLuke MasonSara AmbrosinoRosemary HoltSven BölteJan K BuitelaarJilly NaaijenPublished in: Translational psychiatry (2023)
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.
Keyphrases
- autism spectrum disorder
- intellectual disability
- genome wide
- copy number
- genome wide identification
- gene expression
- resting state
- white matter
- computed tomography
- functional connectivity
- magnetic resonance imaging
- dual energy
- contrast enhanced
- genome wide analysis
- multiple sclerosis
- cerebral ischemia
- transcription factor
- mass spectrometry
- atomic force microscopy