GABAergic regulation of auditory repetition suppression in adults with and without Autism Spectrum Disorder

Suppressing responses to repetitive sounds, while staying vigilant to rare sounds, is a cross-species trait vital for survival, which is altered in autism spectrum disorder (ASD). Preclinical models implicate {Upsilon}-aminobutyric acid (GABA) in this process. Although differences in GABA genes, post-mortem markers and bulk tissue GABA levels have been observed in ASD, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. Here, we directly evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD). Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. We first established that temporal mismatch negativity was comparable between control participants and those with ASD. Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in controls. An individual sensitivity index of arbaclofen-elicited shift in suppression strongly correlated with autistic symptomatology measured using the Autism Quotient. Thus, our results confirm: GABAergic dysfunction is fundamental to the neurophysiology of auditory sensory processing alterations in ASD, which can be modulated by targeting GABAB activity; and these GABA-dependent sensory differences may be upstream of more complex autistic phenotypes. One Sentence SummaryDifferences in GABAergic function are fundamental to autistic (auditory) sensory neurobiology; but are modulated by targeting GABAB.