Elsevier

NeuroImage

Volume 86, 1 February 2014, Pages 28-34
NeuroImage

Review
Decreased left perisylvian GABA concentration in children with autism and unaffected siblings

https://doi.org/10.1016/j.neuroimage.2013.01.045Get rights and content

Abstract

Imbalanced levels of excitation and inhibition (E/I) have been proposed to account for various behavioral and electrophysiological phenotypes in autism. Although proton magnetic resonance spectroscopy (1H-MRS) studies have been published on various metabolite levels in autism, including glutamate, the major excitatory neurotransmitter, few 1H-MRS studies have yet been conducted the major inhibitory neurotransmitter GABA.

Seventeen individuals with autism spectrum disorders (ASD) participated in a single-voxel, point resolved spectroscopy (PRESS) study conducted on a 3 T magnet. Data were also acquired on 14 unaffected siblings of children with autism, and 17 age- and gender-matched healthy control subjects. GABA concentration was measured along with Creatine (Cr) in a single voxel aligned with the auditory cortex in the perisylvian region of the left hemisphere.

The ratio of GABA to Cr was significantly lower in the ASD group than the control subjects. Siblings also exhibited lower GABA/Cr ratios compared to controls. Cr concentration did not differ between groups. The volumes of gray matter, white matter and CSF did not differ between groups in the whole brain or within the spectroscopy voxel.

Reduced auditory GABA concentration in ASD is consistent with one previous MRS study of GABA concentration in the frontal lobe in autism, suggesting that multiple neocortical areas may be involved. Lower GABA levels are consistent with theories of ASD as a disorder involving impaired inhibitory neurotransmission and E/I imbalance. The reduction in unaffected siblings suggests that it may be a heritable biomarker, or endophenotype, of autism.

Highlights

► GABA was assessed in subjects with autism, unaffected siblings and controls. ► Concentration was assessed in the left perisylvian region using MEGAPRESS. ► The autism and sibling groups exhibited significantly reduced GABA. ► Results are consistent with a heritable deficit in cortical inhibition in autism.

Introduction

Autism spectrum disorders (ASDs), which are characterized by impairments in social interaction, communication, and restricted/stereotyped behaviors, are relatively common, with population prevalence around 1% (Kogan et al., 2009). While medical conditions with known etiology account for up to 10% of cases (e.g., Fragile X syndrome, Tuberous Sclerosis), most cases do not have clear origins (Kielinen et al., 2004, Schaefer and Lutz, 2006).

Gamma-amino-butyric-acid (GABA), the major inhibitory transmitter in the CNS, has been implicated in the pathophysiology of autism (Coghlan et al., 2012). Evidence for GABAergic inhibitory problems in ASD converges from a variety of scientific disciplines and has also been of interest for some time (e.g., Hussman, 2001). Previous studies have reported reduced GABAA-receptor binding in hippocampus, neocortex and cerebellum (Blatt et al., 2001, Fatemi et al., 2009). Reduced protein levels of several GABA receptor subunits have also been reported in frontal cortex in ASD (Fatemi et al., 2009).

Genetic evidence also implicates GABA. GABA receptor genes, most notably GABRB3, have been of significant interest in autism (e.g., Ma et al., 2005). Cook et al. (1998) reported linkage disequilibrium between autism and a marker for GABRB3 in the 15q11–13 chromosome region, a result replicated by some studies (e.g., Buxbaum et al., 2002), but not by others (e.g., Salmon et al., 1999). Other GABA receptor subunit genes have also been identified as potential candidates for autism-related pathology (Ma et al., 2005). Partial duplication of 15q is observed in a number of cases of ASD, a region including several GABA genes (e.g., GABRB3: Buxbaum et al., 2002). Messenger RNA levels of glutamate decarboxylase (GAD), the enzyme that converts glutamate to GABA and is highly related to intraneuronal GABA, have been reported to be reduced by about 40% in cerebellar Purkinje cells in persons with autism (Yip et al., 2007) and up to 50% in parietal and/or cerebellar tissues (Fatemi et al., 2002). A region on chromosome-2 encodes GAD67, with significant linkage reported in two separate autism studies (International Molecular Genetic Study of Autism, C., 2001, Martin et al., 2000).

In-vivo GABA concentration measurement in human subjects is possible using 1H-MRS methods, although to date there has only been a single study in ASD (Harada et al., 2010). This is likely due to the challenge inherent in spectral editing techniques necessitated by overlap of the GABA resonances with other metabolites in unedited spectra (Puts and Edden, 2012). Harada et al. (2010) reported reduced GABA concentration in the frontal lobe, but not striatum, in ASD. Some of the subjects in that study, however, were sedated with triclofos, a GABA agonist, which might complicate interpretation of the results. Although elevated, rather than reduced, plasma GABA levels have been found previously in ASD (Dhossche et al., 2002), it is unclear if there is a straightforward relationship between plasma and CNS levels of GABA, because GABA does not cross the blood–brain barrier.

The current study was designed to explore the hypothesis that decreased GABA concentration would be found in the auditory cortex and surrounding left perisylvian region in persons with ASD. Based in part on our own prior work, the auditory cortex is a location that exhibits electrophysiological deficits in gamma-band oscillations in ASD (Gandal et al., 2010, Rojas et al., 2008, Rojas et al., 2011, Wilson et al., 2007), which have been closely linked to GABAergic mechanisms and inhibitory interneurons (Bartos et al., 2007, Brunel and Wang, 2003). In addition, structural abnormalities of the perisylvian region have been noted in ASD, including alteration in the normal asymmetry of the planum temporale (Herbert et al., 2002, Rojas et al., 2005) and pars opercularis (Herbert et al., 2002). Functional MRI studies have indicated anomalous activation of Broca's area and reductions in left-right asymmetry in frontal language regions (Knaus et al., 2008, Knaus et al., 2010). We also predicted that GABA concentration would be lower in siblings of persons with ASD, based on evidence that auditory gamma-band abnormalities are also present in first-degree relatives of individuals with ASD (Rojas et al., 2008, Rojas et al., 2011) and the high heritability of autism (Bailey et al., 1995).

Section snippets

Participants

A total of 48 subjects underwent un-sedated MRI scans in this study. Seventeen individuals with ASD participated who met DSM-IV clinical criteria for ASD (Autistic Disorder, N = 9, Asperger's Disorder, N = 7 and PDD-NOS, N = 1), as applied by an experienced clinical psychologist (SH). In addition, ASD participants also met criteria on the Autism Diagnostic Observation Schedule (Lord et al., 2000), and either the Autism Diagnostic Interview, Revised (ADI-R: Lord et al., 1994) or the Social

Demographics and behavioral data

One-way ANOVAs was used to examine demographic variables for significant differences. There were no significant differences in age between groups, F(2,45) = .76, p = .48. Age has previously been found to correlate with some MRS metabolites in some published studies, so we computed Pearson r correlation coefficients between the 2 MRS variables and age. Neither was significantly correlated with age (GABA +/Cr: r(48) = .06, p = .69; Cr: r(48) =  .05, p = .71).

A chi-square test was used to assess gender

Discussion

Our hypotheses of reduced GABA concentration in the auditory cortex of persons with ASD and unaffected siblings of persons with ASD were supported. The lower GABA +/Cr ratio in ASD is partly consistent with one previous study reporting GABA changes in the frontal lobe, but not the lenticular nuclei (Harada et al., 2010). In the Harada et al. study, GABA concentration, in addition to quantification relative to an internal water standard, was also expressed as a ratio to n-acetyl-aspartate (NAA)

Conclusions

GABA +/Cr ratios were significantly lower in individuals with ASD and in unaffected siblings of persons with ASD, consistent with predictions of impaired inhibitory neurotransmission in the disorder and with the E/I imbalance theory of ASD (Rubenstein and Merzenich, 2003). The presence of the finding in siblings suggests that reduced GABA may be a heritable biomarker. Although none of the participants in the current study had a history of seizure disorder, the prevalence of epilepsy in ASD is as

Acknowledgments

Supported by NIH/NIMH grants R01 MH082820, R01 MH082820-03S1 and by NIH/NCRR Colorado CTSI grant UL1 RR025780. Contents are the authors' sole responsibility and do not necessarily represent official NIH views. The authors of the manuscript declare that they have no conflict of interests to report regarding this manuscript.

References (70)

  • M.J. Gandal et al.

    Validating γ oscillations and delayed auditory responses as translational biomarkers of autism

    Biol. Psychiatry

    (2010)
  • N. Goto et al.

    No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage first-episode schizophrenia

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2010)
  • A.Y. Hardan et al.

    An MRI and proton spectroscopy study of the thalamus in children with autism

    Psychiatry Res.

    (2008)
  • T.A. Knaus et al.

    Language laterality in autism spectrum disorder and typical controls: a functional, volumetric, and diffusion tensor MRI study

    Brain Lang.

    (2010)
  • J.G. Levitt et al.

    Proton magnetic resonance spectroscopic imaging of the brain in childhood autism

    Biol. Psychiatry

    (2003)
  • D.Q. Ma et al.

    Identification of significant association and gene–gene interaction of GABA receptor subunit genes in autism

    Am. J. Hum. Genet.

    (2005)
  • N.A. Puts et al.

    In vivo magnetic resonance spectroscopy of GABA: a methodological review

    Prog. Nucl. Magn. Reson. Spectrosc.

    (2012)
  • G.B. Schaefer et al.

    Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders

    Genet. Med.

    (2006)
  • D.P. Soares et al.

    Magnetic resonance spectroscopy of the brain: review of metabolites and clinical applications

    Clin. Radiol.

    (2009)
  • T.W. Wilson et al.

    Children and adolescents with autism exhibit reduced MEG steady-state gamma responses

    Biol. Psychiatry

    (2007)
  • B.S. Abrahams et al.

    Advances in autism genetics: on the threshold of a new neurobiology

    Nat. Rev. Genet.

    (2008)
  • R. Abramson et al.

    Elevated blood serotonin in autistic probands and their first-degree relatives

    J. Autism Dev. Disord.

    (1989)
  • A. Bailey et al.

    Autism as a strongly genetic disorder: evidence from a British twin study

    Psychol. Med.

    (1995)
  • M. Bartos et al.

    Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks

    Nat. Rev. Neurosci.

    (2007)
  • Z. Bhagwagar et al.

    Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor

    Am. J. Psychiatry

    (2004)
  • G.J. Blatt et al.

    Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study

    J. Autism Dev. Disord.

    (2001)
  • N. Brunel et al.

    What determines the frequency of fast network oscillations with irregular neural discharges? I. Synaptic dynamics and excitation-inhibition balance

    J. Neurophysiol.

    (2003)
  • J.D. Buxbaum et al.

    Association between a GABRB3 polymorphism and autism

    Mol. Psychiatry

    (2002)
  • D. Dhossche et al.

    Elevated plasma gamma-aminobutyric acid (GABA) levels in autistic youngsters: stimulus for a GABA hypothesis of autism

    Med. Sci. Monit.

    (2002)
  • L.M. Dunn

    PPVT-III: Peabody Picture Vocabulary Test-Third Edition

    (1997)
  • C.N. Epperson et al.

    Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study

    Arch. Gen. Psychiatry

    (2002)
  • S.H. Fatemi et al.

    GABA(A) receptor downregulation in brains of subjects with autism

    J. Autism Dev. Disord.

    (2009)
  • S.D. Friedman et al.

    Gray and white matter brain chemistry in young children with autism

    Arch. Gen. Psychiatry

    (2006)
  • L. Gabis et al.

    1H-magnetic resonance spectroscopy markers of cognitive and language ability in clinical subtypes of autism spectrum disorders

    J. Child Neurol.

    (2008)
  • D.C. Glahn et al.

    Neuroimaging endophenotypes: strategies for finding genes influencing brain structure and function

    Hum. Brain Mapp.

    (2007)
  • Cited by (144)

    • Autism spectrum disorder

      2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second Edition
    View all citing articles on Scopus
    View full text