Reduced GABAergic Action in the Autistic Brain

Abstract

An imbalance between excitatory/inhibitory neurotransmission has been posited as a central characteristic of the neurobiology of autism [1], inspired in part by the striking prevalence of seizures among individuals with the disorder [2]. Evidence supporting this hypothesis has specifically implicated the signaling pathway of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in this putative imbalance: GABA receptor genes have been associated with autism in linkage and copy number variation studies [3-7], fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals [8, 9], and GABAergic signaling is disrupted across heterogeneous mouse models of autism [10]. Yet, empirical evidence supporting this hypothesis in humans is lacking, leaving a gulf between animal and human studies of the condition. Here, we present a direct link between GABA signaling and autistic perceptual symptomatology. We first demonstrate a robust, replicated autistic deficit in binocular rivalry [11], a basic visual function that is thought to rely on the balance of excitation/inhibition in visual cortex [12-15]. Then, using magnetic resonance spectroscopy, we demonstrate a tight linkage between binocular rivalry dynamics in typical participants and both GABA and glutamate levels in the visual cortex. Finally, we show that the link between GABA and binocular rivalry dynamics is completely and specifically absent in autism. These results suggest a disruption in inhibitory signaling in the autistic brain and forge a translational path between animal and human models of the condition.

Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABAA receptors

“…On the other hand, α5-PAMs might help to control enhanced E/I balance and associated unspecific synaptic plasticity. For example, it was suggested that autism spectrum disorder (ASD) is associated with enhanced glutamate transmission, reduced GABA transmission, and disturbed cortical connectivity, which might be partially mediated via reduced α5-GABA A R activity 52,53 . Interestingly, α5 knockout mice have been reported to exhibit ASD-like behavioral phenotypes, consistent with a major role of α5-GABA A Rs in the control of input-specific NMDAR-dependent synaptic plasticity 54,55 .…”

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

“…For example, decreased GABA levels in individuals with ASD compared to controls have been reported in motor (Gaetz et al, 2014) and auditory cortex (Gaetz et al, 2014;Rojas, Singel, Steinmetz, Hepburn, & Brown, 2014), and in the ACC (Cochran et al, 2015), although Brix et al (2015) found no differences in GABA levels in the ACC. Other regions, such as the occipital cortex show no differences in GABA levels between participants with and without ASD (Gaetz et al, 2014;Robertson et al, 2015).…”

“…However, other studies have found decreased glutamate/Glx in ASD in regions including the ACC (Bernardi et al, 2011;van Elst, Maier, Fangmeier, & Endres, 2014) the basal ganglia (Horder et al, 2013); frontal and occipital cortex, the cerebellum (Devito et al, 2007) and white matter (Corrigan et al, 2013). Yet other studies have found no significant differences in glutamate / Glx levels between individuals with and without ASD in several different brain regions including parietal lobes (Horder et al, 2013;Page et al, 2006), frontal lobes (Horder et al, 2013) temporal lobes (Devito et al, 2007), and occipital lobes (Robertson, Ratai, & Kanwisher, 2015); the thalamus (Bernardi et al, 2011;Doyle-Thomas et al, 2014;Hardan et al, 2008); hippocampus (Joshi et al, 2012);and cerebellum (van Elst et al, 2014). Therefore, the literature regarding glutamate/Glx levels in ASD is mixed.…”

“…Three of these studies have found significant differences in binocular rivalry in ASD compared to neurotypical individuals (Freyberg et al, 2015;Robertson, Kravitz, Freyberg, Baron-Cohen, & Baker, 2013;Robertson et al, 2015), and one study found no differences (Said, Egan, Minshew, Behrmann, & Heeger, 2013). Where differences between individuals with and without ASD have been found, data concur to suggest 'slower' binocular rivalry in ASD, which is characterised by a reduced switching rate due to a longer time perceiving mixed percepts (Freyberg et al, 2015;Robertson et al, 2013Robertson et al, , 2015. Robertson and colleagues (2015) report that there is a decreased rate of perceptual suppression in ASD, which manifests as a larger amount of time perceiving a mixed percept, and less time perceiving an individual percept.…”

ASD Validity

“…Mullins et al (2016) posited that mutations in the FMR1 gene and TSC genes disrupt long-term depression (LTD) and long-term potentiation (LTP), and therefore, these mutations in ASD cause atypical LTP and LTD processes that impair the excitation-inhibition balance in brain development and function which determines ASD (Mullins et al 2016). Robertson et al (2015) claimed that the Bprime suspectŝ ingle cause for ASD was disrupted GABAergic signaling that impaired neurodevelopment and cortical computations. However, Estes and McAllister (2015) theorized that ASD was caused by atypical immune system factors that converged on the MEF2 and mTOR signaling hubs and thus disrupted the brain's developmental synaptic function and plasticity.…”