Research Article

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

Sophie E. Holmes, Matthew J. Girgenti, Margaret T. Davis, Robert H. Pietrzak, Nicole DellaGioia, Nabeel Nabulsi, David Matuskey, Steven Southwick, Ronald S. Duman, Richard E. Carson, John H. Krystal, Irina Esterlis, and the Traumatic Stress Brain Study Group
PNAS August 1, 2017 114 (31) 8390-8395; first published July 17, 2017; https://doi.org/10.1073/pnas.1701749114

  1. Edited by Marcus E. Raichle, Washington University in St. Louis, St. Louis, MO, and approved June 12, 2017 (received for review February 6, 2017)

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Article Figures & SI

Figures

  • Fig. 1.
    Fig. 1.

    mGluR5 availability in PTSD: PET findings. (A) Parametric [18F]FPEB VT images overlaid onto T1-weighted MRI in template space for a representative PTSD subject (Upper: 29-y-old male) and HC subject (Lower: 27-y-old male) in transaxial, coronal, and sagittal planes. (B) mGluR5 availability in PTSD (n = 16) compared with HC (n = 16). (C) Correlation between mGluR5 availability in the dlPFC and scores on the avoidance subscale of the PCL. Error bars represent SD. P values obtained from exploratory MANCOVAs. Pearson’s r was used for correlation analysis. *Significant at P < 0.05.

  • Fig. 2.
    Fig. 2.

    RT-PCR analysis of selected genes in control and PTSD subgenual PFC. Dotted lines indicate control (no change). Error bars represent SEM. *Significant at P < 0.05 (independent samples t tests).

Tables

  • Table 1.

    Regional [18F]FPEB VT (mGluR5 availability) for PTSD vs. HC

    RegionHC (n = 16)PTSD (n = 16)Difference, %Cohen’s dP value*
    dlPFC30.25 (5.78)36.40 (9.67)20.40.770.034†
    OFC28.07 (5.23)33.71 (9.45)20.10.740.044†
    vmPFC29.73 (5.48)35.16 (9.54)18.20.700.052
    Parietal cortex27.06 (5.12)32.44 (9.40)19.90.710.050
    Temporal cortex29.44 (5.52)34.30 (9.09)16.50.650.072
    Occipital cortex26.73 (5.11)31.38 (8.47)17.40.660.066

    • Values are given as mean (SD).

    • ↵* P values obtained from MANCOVAs, with age and sex as covariates.

    • ↵† Significant at P < 0.05.

  • Table S1.

    Subcortical [18F]FPEB VT values (mGluR5 availability) for PTSD vs. HC subjects

    RegionHC (n = 16)PTSD (n = 16)Difference, %Cohen’s dP value*
    Caudate25.29 (5.11)29.20 (8.74)15.50.550.13
    Putamen25.95 (4.64)29.76 (7.68)14.70.600.10
    Ventral striatum29.59 (5.39)36.03 (7.16)21.70.990.007†
    Amygdala25.76 (5.01)28.69 (7.77)11.30.450.22
    Hippocampus22.69 (4.88)25.05 (7.07)10.40.390.28

    • Values are given as mean (SD).

    • ↵* P values obtained from independent samples t tests.

    • ↵† Significant at P < 0.05.

  • Table S2.

    qRT-PCR fold changes in PTSD and non-PTSD subgenual PFC

    GeneFold changeSEMtCohen’s dP value*
    FKBP5−3.51.113.384.46<0.001†
    Shank1+3.81.22.500.810.02†
    mGluR5+1.10.50.210.080.83
    Homer+1.11.61.440.450.16
    FKBP1a+1.00.090.420.050.934
    FKBP8+1.00.020.190.400.721

    • ↵* P values obtained from independent samples t tests.

    • ↵† Significant at P < 0.05.

  • Table S3.

    Comorbid diagnoses, manner, and cause of death for PTSD group

    SubjectDSM-IV diagnosesManner of deathCause of death
    1PTSD; ADR; ODCAccidentalDrug overdose
    2PTSD; ADRNaturalUpper airway obstruction
    3PTSDNaturalASCVD
    4PTSD; ODCAccidentalDrug overdose
    5PTSD; ADC; OACNaturalASCVD
    6PTSD; ADCAccidentalTrauma
    7PTSDSuicideIncised wounds
    8PTSD; ODC; ODRAccidentalDrug overdose
    9PTSD; ADC; ODCNaturalASCVD
    10PTSD; ADCNaturalASCVD
    11PTSD; AACAccidentalTrauma
    12PTSD; ADC; ODR; OARNaturalCardiomegaly
    13PTSD; AARNaturalASCVD
    14PTSD; AARNaturalArrhythmogenic ventricular dysphasia
    15PTSD; ADR; ODRNaturalPulmonary embolism
    16PTSD; AAR; ODRUndeterminedDrug overdose
    17PTSD; ADC; OACAccidentalTrauma
    18PTSD; AAR; ODRNaturalVascular heart disease
    19PTSD; ADC; ODCNaturalASCVD

    • AAC, alcohol abuse (current at time of death); AAR, alcohol abuse (in remission at time of death); ADC, alcohol dependence (current at time of death); ADR, alcohol dependence (in remission at time of death); ASCVD, atherosclerotic cardiovascular disease; OAC, other substance abuse (current); OAR, other substance abuse (remission); ODC, other substance dependence (current); ODR, other substance dependence (in remission at time of death).

  • Table S4.

    [18F]FPEB VT values (mGluR5 availability) for smokers and nonsmokers in PTSD and HC groups

    RegionHCPTSD
    Smokers (n = 4)Nonsmokers (n = 12)P value*Smokers (n = 4)Nonsmokers (n = 12)P value*
    dlPFC26.51 (7.69)31. 50 (4.76)0.1434.47 (3.14)38.07 (10.16)0.56
    vmPFC26.94 (7.43)30.67 (4.69)0.2532.98 (2.89)36.80 (10.12)0.54
    OFC25.00 (6.88)29.09 (4.45)0.1831.95 (3.00)35.26 (10.03)0.59
    Parietal24.33 (6.24)27.97 (4.65)0.2328.94 (1.09)34.37 (9.92)0.37
    Temporal26.45 (7.12)30.43 (4.84)0.5232.12 (2.30)35.92 (9.63)0.52
    Occipital32.71 (5.95)27.74 (4.63)0.1828.48 (2.28)33.07 (8.90)0.40

    • Values are given as mean (SD).

    • ↵* P values obtained from independent samples t tests.

  • Table S5.

    PET study participant characteristics

    VariablePTSD group (n = 16)HC group (n = 16)tP value*
    Sex (male:female)6:106:10——
    Age, y36.5 (8.8)36.4 (11.0)−0.110.68
    BMI (kg/m2)29.5 (6.3)27.8 (4.4)0.900.38
    No. of smokers44——
    Age at onset, y14.4 (8.0)———
    Duration of illness, y19.6 (10.8)———
    CAPS70.2 (25.4)———
    PCL54.1 (12.7)———
    MADRS22.0 (7.7)———
    HAM-D16.3 (8.8)———
    Injected mass of FPEB (µg)0.35 (0.42)0.32 (016)0.290.78
    Injected dose (MBq)168 (0.85)159 (0.89)0.850.40

    • Values are given as mean (SD). BMI, body mass index; HAM-D, Hamilton Depression Rating Scale; MADRS, Montgomery–Asberg Depression Scale.

    • ↵* P values obtained from independent samples t tests.

  • Table S6.

    Characteristics of postmortem samples

    VariableHC tissue (n = 19)PTSD tissue (n = 19)tP value*
    Sex (male:female)9:109:10——
    Age, y50.1 (10.4)47.6 (10.9)0.720.48
    PMI18.9 (7.1)15.6 (5.8)1.540.13
    pH6.4 (0.3)6.6 (0.4)1.190.24
    RIN7.4 (1.0)7.9 (1.0)1.700.10

    • Values are given as mean (SD). RIN, RNA integrity number.

    • ↵* P values obtained from independent samples t tests.

  • Table S7.

    Comorbid diagnoses, manner, and cause of death for comparison group

    SubjectDSM-IV diagnosesManner of deathCause of death
    1NoneNaturalPulmonary embolism
    2NoneAccidentalPeritonitis
    3NoneNaturalPulmonary embolism
    4NoneAccidentalTrauma
    5NoneNaturalPulmonary embolism
    6NoneNaturalCongestive heart failure
    7NoneUndeterminedUndetermined
    8NoneNaturalASCVD
    9NoneNaturalCardiac tampanade
    10NoneNaturalASCVD
    11NoneNaturalASCVD
    12NoneNaturalPulmonary embolism
    13NoneNaturalASCVD
    14NoneNaturalAcute endocarditis
    15NoneNaturalPulmonary embolism
    16NoneNaturalInterstitial myocardial fibrosis
    17NoneNaturalMyocardial infarct
    18NoneAccidentalTrauma
    19NoneNaturalASCVD

    • ASCVD, atherosclerotic cardiovascular disease.

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Altered mGluR5 markers in PTSD
Sophie E. Holmes, Matthew J. Girgenti, Margaret T. Davis, Robert H. Pietrzak, Nicole DellaGioia, Nabeel Nabulsi, David Matuskey, Steven Southwick, Ronald S. Duman, Richard E. Carson, John H. Krystal, Irina Esterlis, the Traumatic Stress Brain Study Group
Proceedings of the National Academy of Sciences Aug 2017, 114 (31) 8390-8395; DOI: 10.1073/pnas.1701749114
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