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

Abstract

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.

Bridging the translational neuroscience gap: Development of the ‘shiftability’ paradigm and an exemplar protocol to capture psilocybin-elicited ‘shift’ in neurobiological mechanisms in autism

“…A conventional auditory oddball paradigm (mismatch negativity, MMN) 62 will be used to passively measure 'repetition suppression' (or habituation) to repetitive auditory stimuli and response to an unexpected 'deviant' stimulus (the eventrelated mismatch negativity MMN response). We and others have observed less repetition suppression in both eight-month-old infants who go on to receive a diagnosis or autism, and adults with a diagnosis of autism 24,30 . Thus, this signal appears linked to autism across infancy to maturity.…”

“…We have also used EEG recordings during sensory stimulation to capture response to GABAB receptor agonist, arbaclofen. We have been able to quantify individual 'shifts' in these measures in response to drug challenge and differences at group-level between autistic and non-autistic participants 10,30 . The range of measures used to capture 'shift' and their target level of brain organisation is shown in Figure 1.…”

Habituation of auditory responses in young autistic and neurotypical children

“…Within this framework, repeated and/or irrelevant sensory inputs might not be inhibited in autism as they would be in TD, resulting in a more robust neural response to these repeated stimuli (Ethridge et al, 2016;Kolesnik et al, 2019). There is evidence from typically developing individuals linking inhibitory processing and habituation (Palermo et al, 2011), and recent evidence suggests that arbaclofen, a GABA receptor agonist, appears to enhance repetition suppression in autistic adults (Huang et al, 2023). Moreover, decreased inhibition in the auditory cortex has been shown in animal models to directly lead to loudness hyperacusis, a form of sound intolerance (McGill et al, 2023).…”

Retinal GABAergic Alterations in Adults with Autism Spectrum Disorder

“…Correlations, however, are not causal. A more direct way to establish that a particular neurosignaling system is involved in specific sensory mechanisms is to challenge it through pharmacological modulation and observe a change in function ( Whelan et al, 2023 ). We have adopted this approach and previously shown that a single dose of the GABA type B (GABA B ) receptor agonist arbaclofen (STX209) enhances suppression of cortical electroencephalogram (EEG) responses to sensory stimuli in both the visual and auditory domains in individuals with ASD, but does the opposite in nonautistic people ( Huang et al, 2022 ).…”