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Reduced GABAergic Action in the Autistic Brain

2015; Elsevier BV; Volume: 26; Issue: 1 Linguagem: Inglês

10.1016/j.cub.2015.11.019

1879-0445

Caroline E. Robertson, Eva‐Maria Ratai, Nancy Kanwisher,

Obsessive-Compulsive Spectrum Disorders

An imbalance between excitatory/inhibitory neurotransmission has been posited as a central characteristic of the neurobiology of autism [1Rubenstein J.L.R. Merzenich M.M. Model of autism: increased ratio of excitation/inhibition in key neural systems.Genes Brain Behav. 2003; 2: 255-267Crossref PubMed Scopus (1716) Google Scholar], inspired in part by the striking prevalence of seizures among individuals with the disorder [2Canitano R. Epilepsy in autism spectrum disorders.Eur. Child Adolesc. Psychiatry. 2007; 16: 61-66Crossref PubMed Scopus (192) Google Scholar]. 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 [3Sanders S.J. Ercan-Sencicek A.G. Hus V. Luo R. Murtha M.T. Moreno-De-Luca D. Chu S.H. Moreau M.P. Gupta A.R. Thomson S.A. et al.Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.Neuron. 2011; 70: 863-885Abstract Full Text Full Text PDF PubMed Scopus (945) Google Scholar, 4Shao Y. Cuccaro M.L. Hauser E.R. Raiford K.L. Menold M.M. Wolpert C.M. Ravan S.A. Elston L. Decena K. Donnelly S.L. et al.Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes.Am. J. Hum. Genet. 2003; 72: 539-548Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 5Ma D.Q. Whitehead P.L. Menold M.M. Martin E.R. Ashley-Koch A.E. Mei H. Ritchie M.D. Delong G.R. Abramson R.K. Wright H.H. et al.Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.Am. J. Hum. Genet. 2005; 77: 377-388Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, 6Chen C.-H. Huang C.-C. Cheng M.-C. Chiu Y.-N. Tsai W.-C. Wu Y.-Y. Liu S.-K. Gau S.S.-F. Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders.Mol. Autism. 2014; 5: 36Crossref PubMed Scopus (43) Google Scholar, 7Piton A. Jouan L. Rochefort D. Dobrzeniecka S. Lachapelle K. Dion P.A. Gauthier J. Rouleau G.A. Analysis of the effects of rare variants on splicing identifies alterations in GABAA receptor genes in autism spectrum disorder individuals.Eur. J. Hum. Genet. 2013; 21: 749-756Crossref PubMed Scopus (45) Google Scholar], fewer GABA receptor subunits have been observed in the post-mortem tissue of autistic individuals [8Fatemi S.H. Reutiman T.J. Folsom T.D. Thuras P.D. GABA(A) receptor downregulation in brains of subjects with autism.J. Autism Dev. Disord. 2009; 39: 223-230Crossref PubMed Scopus (315) Google Scholar, 9Oblak A.L. Gibbs T.T. Blatt G.J. Reduced GABAA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism.Brain Res. 2011; 1380: 218-228Crossref PubMed Scopus (116) Google Scholar], and GABAergic signaling is disrupted across heterogeneous mouse models of autism [10Gogolla N. Leblanc J.J. Quast K.B. Südhof T.C. Fagiolini M. Hensch T.K. Common circuit defect of excitatory-inhibitory balance in mouse models of autism.J. Neurodev. Disord. 2009; 1: 172-181Crossref PubMed Scopus (428) Google Scholar]. 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 [11Robertson C.E. Kravitz D.J. Freyberg J. Baron-Cohen S. Baker C.I. Slower rate of binocular rivalry in autism.J. Neurosci. 2013; 33: 16983-16991Crossref PubMed Scopus (95) Google Scholar], a basic visual function that is thought to rely on the balance of excitation/inhibition in visual cortex [12Laing C.R. Chow C.C. A spiking neuron model for binocular rivalry.J. Comput. Neurosci. 2002; 12: 39-53Crossref PubMed Scopus (247) Google Scholar, 13Seely J. Chow C.C. Role of mutual inhibition in binocular rivalry.J. Neurophysiol. 2011; 106: 2136-2150Crossref PubMed Scopus (67) Google Scholar, 14Said C.P. Heeger D.J. A model of binocular rivalry and cross-orientation suppression.PLoS Comput. Biol. 2013; 9: e1002991Crossref PubMed Scopus (73) Google Scholar, 15van Loon A.M. Knapen T. Scholte H.S. St John-Saaltink E. Donner T.H. Lamme V.A.F. GABA shapes the dynamics of bistable perception.Curr. Biol. 2013; 23: 823-827Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar]. 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.