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

This study looked at brain chemistry differences in autism, focusing on two important brain chemicals: glutamate (excitatory) and GABA (inhibitory). Researchers studied genetic data and brain scans from 359 autistic people and 279 non-autistic people. They found that genes related to glutamate were linked to autism symptom severity. Brain regions with more of these chemical systems showed structural differences between autistic and non-autistic brains, suggesting these brain chemicals play important but complex roles in autism.

This study examined the excitatory/inhibitory (E/I) imbalance hypothesis in autism using genetic and brain imaging data from 359 autistic participants and 279 neurotypical controls aged 6-30 years. Researchers analyzed glutamate and GABA gene-sets in relation to autism symptoms and cortical thickness differences. Results showed glutamate gene-sets were associated with all autism symptom severity scores on standardized assessments. In adolescents and adults, brain regions with higher expression of glutamate and GABA genes showed greater cortical thickness differences between autistic and neurotypical participants, but in opposing directions.

The findings suggest complex relationships between E/I-related genetics, autism symptom profiles, and brain structure alterations, with differential roles for glutamate and GABA systems.

Findings support the E/I imbalance hypothesis in autism and suggest glutamate and GABA systems may be important therapeutic targets. The differential associations with symptom severity and brain structure could inform personalized approaches to understanding and potentially treating autism symptoms, particularly those related to sensory processing differences.

The abstract does not specify methodological limitations, sample characteristics beyond age range, or potential confounding variables. The study type is unknown, and specific statistical analyses and effect sizes are not reported, limiting interpretation of clinical significance.

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.