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 ϒ-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 Summary Differences in GABAergic function are fundamental to autistic (auditory) sensory neurobiology; but are modulated by targeting GABAB. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03594552 ### Funding Statement This project was funded by an Independent Investigator Award (G.M.M.) from the Brain and Behaviour Research Foundation and by Clinical Research Associates, L.L.C. (CRA), an affiliate of the Simons Foundation. Support is also acknowledged from Autistica (A.C.P.) and the Sackler Institute for Translational Neurodevelopment at Kings College London and EU-AIMS (European Autism Interventions)/EU AIMS-2-TRIALS, an Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 777394. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was granted by Kings College Research Ethics Committee (RESCM-17/18-4081). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data from this study are available on request.