Finding treatments for autism spectrum disorder (ASD) has been challenging because its etiology is so poorly understood. Moreover, there are currently no means to ‘fractionate’ the spectrum into biologically homogeneous ASD subgroups to target with specific interventions. There is hope, however, as genetic, postmortem and preclinical laboratory studies indicate that differences in the brain’s excitatory glutamatergic and inhibitory GABAergic systems may be a core feature of ASD. This is especially true for the inhibitory system, with studies reporting reductions in both GABA_A and GABA_B receptors in postmortem ASD brains^1,2. GABA helps regulate the functional connectivity of brain networks and is implicated in motor and sensory inhibition differences observed in people with ASD compared to their unaffected peers. However, no one has directly tested if there is a difference in the GABAergic control of brain networks and inhibitory function in people with and without ASD. Further, clinical trials aimed at boosting GABAergic function using arbaclofen, a GABA_B receptor agonist, have shown initial promise in some, but not all, individuals with ASD³. This is not unsurprising in a heterogeneous condition like ASD, but also complicates the ability to develop treatments for ASD.

The laboratory of Grainne McAlonan now plans to examine how brain function and inhibitory control responds to activation of GABA_B receptors in adults with and without ASD. McAlonan’s team will use arbaclofen, which is approved for clinical use in humans, to modulate GABA_B receptor activity in individuals with and without ASD. McAlonan’s team will compare a range of responses in both unaffected and affected individuals exposed to low (single oral dose of 15mg) and higher (single oral dose of 30mg) doses of arbaclofen. The response measures that McAlonan’s team will assess include ‘resting-state’ functional magnetic resonance imaging (fMRI) to examine network connectivity, an fMRI ‘Go/No-Go paradigm’ to map motor inhibition, and assessment of visual suppression tested in a series of out-of-scanner tasks. In addition, McAlonan’s group will use magnetic resonance spectroscopy to measure glutamate and GABA levels in visual cortices to determine if baseline metabolite levels are predictive of visual responses mediated by arbaclofen.

If successful, this study will provide additional evidence that GABA_B receptor pathways are treatment targets for ASD. Further, the results of this study will provide a valuable strategy to help stratify individuals with ASD, identifying individuals most likely to respond to arbaclofen and other novel or repurposed compounds that can alter excitatory/inhibitory balance. Such findings will also aid in the development of future substantive clinical trial initiatives in ASD.

References

1. Fatemi S.H. et al. J. Autism Dev. Disord. 39, 223-230 (2009) PubMed
2. Fatemi S.H. et al. Cerebellum 8, 64-69 (2009) PubMed
3. Veenstra-VanderWeele J. et al. Neuropsychopharmacology 42, 1390-1398 (2017) PubMed