Retinal GABAergic Alterations in Adults with Autism Spectrum Disorder

Abstract

Alterations in γ-aminobutyric acid (GABA) have been implicated in sensory differences in individuals with autism spectrum disorder (ASD). Visual signals are initially processed in the retina and in this study we explored the hypotheses that the GABA-dependent retinal response to light is altered in individuals with ASD. Light-adapted electroretinograms (ERGs) were recorded from 61 adults (38 males and 23 females; n = 22 ASD) in response to three stimulus protocols: i) the standard white flash; ii) the standard 30-Hz flickering protocol; iii) the photopic negative response (PhNR) protocol. Participants were administered an oral dose of placebo, 15 or 30 mg of arbaclofen (STX209, GABABagonist) in a randomized, double-blind, cross-over order before the test. At baseline (placebo), the a-wave amplitudes in response to single white flashes were more prominent in ASD, relative to typically developed (TD) participants. Arbaclofen was associated with decrease in the a-wave amplitude in ASD, but an increase in TD, eliminating the group difference observed at baseline. The extent of this arbaclofen-elicited shift significantly correlated with the arbaclofen-elicited shift in cortical responses to auditory stimuli as measured by electroencephalogram in our prior study, and with broader autistic traits measured with the Autism Quotient across the whole cohort. Hence, GABA-dependent differences in retinal light processing in ASD appear to be an accessible component of a wider autistic difference in central processing of sensory information, which may be upstream of more complex autistic phenotypes.Significance StatementOur current study provides the first direct in vivo experimental confirmation that autistic alterations in central GABA function extend to the retina. We show that arbaclofen was associated with reduced flash elicited a-wave amplitude in the electroretinogram (ERG) of autistic individuals but increased amplitude in non-autistic people. The retinal arbaclofen response correlated with previously reported arbaclofen effects on cortical visual and auditory responses in the same individuals. The extent of this differential GABAergic function correlated with the extent of autistic traits captured using the Autism Quotient. Thus, sensory processing differences in autism appear to be upstream of more complex autistic traits and the ERG from the retina is a potentially useful proxy for cross-domain brain GABA function and target engagement.