Research ArticleAutism Spectrum Disorder

GABAA receptor availability is not altered in adults with autism spectrum disorder or in mouse models

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Science Translational Medicine  03 Oct 2018:
Vol. 10, Issue 461, eaam8434
DOI: 10.1126/scitranslmed.aam8434
  • Fig. 1 PET imaging with the [11C]flumazenil and [11C]Ro15-4513 tracers in adults with ASD or control individuals without ASD.

    Estimated group mean for (A) the [11C]flumazenil tracer BPND and (B) the [11C]Ro15-4513 tracer distribution volume (VT) in adults with ASD compared to control individuals without ASD. PET images were normalized into MNI-152 standard space. PET images are displayed overlaid on the 2-mm resolution template anatomical magnetic resonance (MR) image. (A) PET imaging with the [11C]flumazenil tracer revealed GABAA receptor availability in the human brain (n = 15 ASD adults and n = 15 control adults). (B) PET imaging with the [11C]Ro15-4513 tracer showed GABAA receptor availability in the human brain (n = 12 ASD adults and n = 16 control adults). BPND was calculated using stationary wavelet-aided parametric imaging. VT was calculated using the Logan method.

  • Fig. 2 GABAA receptor availability in different regions of the ASD and control brain using the [11C]flumazenil tracer.

    Estimated [11C]flumazenil BPND (mean estimated BPND) in different regions of the brain of adults with ASD (n = 15) and control individuals without ASD (n = 15) in the Stockholm cohort. There was no difference in tracer binding (BPND) between the two groups in any comparison. Error bars show ±1 SEM.

  • Fig. 3 Mean binding of tracer in the gray matter of adults with ASD and control individuals without ASD.

    Scatterplots illustrate (A) the estimated mean binding (BPND) of the [11C]flumazenil tracer in gray matter and (B) the estimated mean binding (VT) of the [11C]Ro15-4513 tracer in gray matter for individual participants in the ASD and control groups. There were no differences in tracer binding between the two groups. There were no evident outliers or subgroups with either tracer.

  • Fig. 4 GABAA receptor availability in different regions of the ASD and control brain using the [11C]Ro15-4513 tracer.

    The mean estimated binding (VT) of the [11C]Ro15-4513 tracer across the whole brain and in different brain regions of adults with ASD (n = 12) and control adults without ASD (n = 16) is shown. Estimated specific binding of the [11C]Ro15-4513 tracer was derived from the 2TCM of PET imaging data. Error bars show ±1 SEM.

  • Fig. 5 GABAA receptor availability in mouse brain tissue using autoradiography.

    (A to D) Illustrations of mouse brain regions of interest (ROIs) overlaid on representative autoradiography images from wild-type (WT) mouse brain are shown. ROIs were defined on the basis of Paxinos and Franklin’s mouse brain atlas. The numbers represent the specific regions that were analyzed. Averages were calculated from both brain hemispheres. (A) 1, frontal cortex; (B) 1, caudate/putamen; 2, cingulate cortex; (C) 1, dorsal hippocampus; 2, amygdala; (D) 1, cerebellum. (E, G, and I) Graphs show specific binding of the [3H]flumazenil tracer to brain tissue from three different mutant mouse models of ASD (16p11.2 deletion, Cntnap2−/−, and Shank3−/−) compared to WT control mice. (F, H, and J) Graphs show specific binding of the [3H]Ro15-4513 tracer to brain tissue from three different mutant mouse models of ASD (16p11.2 deletion, Cntnap2−/−, and Shank3−/−) compared to WT control mice. Bars show the group mean binding signal normalized such that the mean signal in the WT group was 100%. Error bars show SEM.

  • Fig. 6 PMP task undertaken by adults with ASD and control individuals without ASD.

    The contrast-induced motion perceptual impairment ratio in each participant is shown, indicating the degree to which motion perception is impaired by large, high-contrast stimuli. Higher values indicate greater impairment. Impairment is considered a proxy for GABA-mediated inhibition, driven by high contrast, in the visual cortex. The line indicates a ratio of 1.0 representing no impairment. The control group shows greater impairment than does the ASD group; t28 = 2.487, P = 0.022, d = 0.921 (two-tailed t test).

  • Table 1 Participant demographic data and ASD clinical scores for the Stockholm and London cohorts.

    Values are shown as means ± SD. P values are the outcome of independent samples t tests testing for a difference in group means within each study. Clinical scores were not available for control participants. Autism Diagnostic Interview–Revised (ADI-R) scores were not available (NA) for the Stockholm cohort. ADOS, Autism Diagnostic Observation Schedule.

    Stockholm cohort
    [11C]Flumazenil PET imaging study
    London cohort
    [11C]Ro15-4513 PET imaging study
    MeasureControlASDP
    (t test)
    ControlASDP
    (t test)
    Number (male/
    female)
    11/411/4NA16/012/0NA
    Age33.0 ± 9.433.0 ± 9.11.00029.8 ± 9.130.7 ± 8.80.684
    Full-scale IQ113.1 ± 15.4106.9 ± 17.90.318122.7 ± 24.5116.0 ± 13.90.256
    ADI-R (social)NANANANA15.5 ± 6.1NA
    ADI-R
    (communication)
    NANANANA12.1 ± 7.0NA
    ADI-R (repetitive)NANANANA4.5 ± 2.6NA
    ADOS (social)NA7.5 ± 5.1NANA7.7 ± 2.1NA
    ADOS
    (communication)
    NA6.9 ± 3.2NANA3.9 ± 1.8NA

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/10/461/eaam8434/DC1

    Methods

    Fig. S1. Autoradiography in the left and right amygdala of mice.

    Table S1. PET tracer dosing in the two human studies.

    Table S2. Further information on functional outcome (employment status) and medication history in the ASD participants in the two PET studies.

    Table S3. [11C]Flumazenil BPND in the ASD and control groups.

    Table S4. [11C]Ro15-4513 VT in the ASD and control groups.

    Table S5. Sensitivity analysis: [11C]Flumazenil BPND in ASD and control groups using correction for partial volume effects.

    Table S6. Sensitivity analysis: [11C]Flumazenil BPND in ASD and control groups, excluding female participants.

    Table S7. Pearson correlations between cognitive performance and [11C]flumazenil BPND in gray matter.

    Table S8. Source data for autoradiography experiments.

    References (6371)

  • This PDF file includes:

    • Methods
    • Fig. S1. Autoradiography in the left and right amygdala of mice.
    • Table S1. PET tracer dosing in the two human studies.
    • Table S2. Further information on functional outcome (employment status) and medication history in the ASD participants in the two PET studies.
    • Table S3. [11C]Flumazenil BPND in the ASD and control groups.
    • Table S4. [11C]Ro15-4513 VT in the ASD and control groups.
    • Table S5. Sensitivity analysis: [11C]Flumazenil BPND in ASD and control groups using correction for partial volume effects.
    • Table S6. Sensitivity analysis: [11C]Flumazenil BPND in ASD and control groups, excluding female participants.
    • Table S7. Pearson correlations between cognitive performance and [11C]flumazenil BPND in gray matter.
    • Table S8. Source data for autoradiography experiments.
    • References (6371)

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