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

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.

Neuron-Specific Enolase (NSE) as a Biomarker for Autistic Spectrum Disease (ASD)

“…More recent studies integrate data from more than one type of investigations, such the electrophysiological and neurotransmitter data on excitatory/inhibitory balance (E/I on resting EEG), GABA and glutamatergic neurotransmitters, imagistics on cortical thickness and gene expression from various databases, (49)(50)(51)(52), and these findings are adding more pieces to the ASD puzzle. When testing a panel of biomarkers, results show much better specificity and sensitivity, so that a panel of 12 inflammatory and immune biomarkers identified 87% of ASD cases (22), and also an 83.3% sensitivity and 84.6% specificity was attained when proteomics testing and a panel of 9 proteins was employed (53).…”

Ligand‐gated ion channels as potential biomarkers for ADT‐mediated cognitive decline in prostate cancer patients

“…36,37 GABA receptors are LGICs and upon activation, mediate the influx of K +/Ca2+ channels, chloride ion, and G-protein linked intracellular processes, inducing hyperpolarization in postsynaptic neurons. 38,39 Dysfunctional GABA activity can disrupt the excitatory/inhibitory balance in the cortex, 40 representing a core pathophysiological mechanism underlying cognitive decline. 41,42 GABA receptors are the target of many drugs including benzodiazepines and anesthetics 43 that might be useful in ameliorating ADT-mediated cognitive effects.…”

Psychological Theories of Autism: Everything, All at Once, In One Place

“…It is a construct that bestrides conventional notions of a "biological level of analysis" and a "cognitive/algorithmic level of analysis" (Marr, 2010;Morton, 2005). On a biological level, current noise accounts derive from Rubenstein and Merzenich's Excitation-Inhibition Ratio hypothesis (Rubenstein & Merzenich, 2003) and current work exploring the contribution of altered GABAergic function (Hollestein et al, 2023).…”