Research ArticleNEUROSCIENCE

Normal sleep requires the astrocyte brain-type fatty acid binding protein FABP7

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Science Advances  05 Apr 2017:
Vol. 3, no. 4, e1602663
DOI: 10.1126/sciadv.1602663
  • Fig. 1 Effects of a human FABP7 point mutation on FABP7 protein structure.

    The FABP7 protein sequence contains three highly conserved motifs consisting of β sheets across FABP types. T61 is flanked by NLS and NES regions. T61 is located adjacent to F57, a site important for generating the NLS with the K21 domain that interacts with HSL. Upon ligand binding (that is, with DHA), a 3D conformational shift in the protein generates an NLS with K21 in WT FABP7, which is disrupted by the T61M variant, affecting nuclear localization and lipid-targeted transcriptional cascades.

  • Fig. 2 The FABP7 T61M missense mutation is associated with fragmented sleep in humans.

    (A and B) Sleep bout duration (A) was significantly decreased and sleep bout frequency (B) was significantly increased in T61M carriers (n = 29) versus noncarriers (n = 265). (C) Wake bout duration was not affected by the T61M variant. (D) Wake bout frequency was significantly higher in T61M carriers versus noncarriers. *P < 0.05, **P < 0.01. Data are from the 7-day average of 24-hour bins. Error bars represent SEM.

  • Fig. 3 The human FABP7 point mutation phenotype is recapitulated in Fabp7 KO mice, which also showed sleep fragmentation.

    (A) NREM bout duration was significantly lower in Fabp7 KO mice (n = 8) compared to WT littermates (n = 7) during the dark phase [Zeitgeber time (ZT) 12 to ZT 24] but was unaffected during the light phase (ZT 0 to ZT 12). (B) NREM bout frequency was significantly higher in Fabp7 KO mice compared to WT littermates during the dark phase (ZT 12 to ZT 24) but was unaffected during the light phase (ZT 0 to ZT 12). (C) REM bout duration was not affected in Fabp7 KO mice compared to WT mice. (D) REM bout frequency was significantly higher in Fabp7 KO mice compared to WT littermates during the dark phase (ZT 12 to ZT 24). (E) Wake bout duration was significantly lower in Fabp7 KO mice compared to WT during the dark phase (ZT 12 to ZT 24) but was unaffected during the light phase (ZT 0 to ZT 12). (F) Wake bout frequency was significantly higher in Fabp7 KO mice compared to WT during the dark phase (ZT 12 to ZT 24) but was unaffected during the light phase (ZT 0 to ZT 12). (G) The number of short wake bouts was increased in Fabp7 KO mice compared to WT (ZT 12 to ZT 24). (H) The number of NREM to wake (N→W), wake to NREM (W→N), NREM to REM (N→R), and REM to wake (R→W) transitions was increased in Fabp7 KO mice compared to WT mice (ZT 12 to ZT 24). *P < 0.05, **P < 0.01. Error bars represent SEM.

  • Fig. 4 Overexpression of FABP7.T61M mutation in astrocytes fragments sleep in Drosophila.

    Daytime (A) and nighttime (B) sleep was fragmented in flies overexpressing FABP7.T61M compared to FABP7.WT using an astrocyte-specific (Alrm-Gal4) driver. Total sleep, bout duration, maximum bout duration, and frequency of bouts are shown. *P < 0.05, ***P < 0.001, n = 32 flies (WT) and 27 flies (T61M). Error bars represent SEM.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/4/e1602663/DC1

    table S1. Age, body mass index, and sleepiness comparison between FABP7.T61M carriers and noncarriers.

    table S2. Health status comparison between FABP7.T61M carriers and noncarriers.

    fig. S1. Baseline total sleep-wake time is not affected in Fabp7 KO mice.

    fig. S2. Locomotor running wheel activity is not affected in Fabp7 KO mice.

    fig. S3. REM sleep time is increased in Fabp7 KO mice during the recovery period following sleep deprivation.

    fig. S4. Overexpression of FABP7.T61M mutation in astrocytes fragments wake only during the daytime in Drosophila.

    fig. S5. Overexpression of FABP7.T61M mutation in astrocytes in male flies also fragments sleep.

    fig. S6. Overexpression of FABP7.T61M mutation in astrocytes in male flies also fragments wake.

    fig. S7. Conditional overexpression of FABP7.T61M mutation in glial cells of adult male flies also fragments sleep in Drosophila.

  • Supplementary Materials

    This PDF file includes:

    • table S1. Age, body mass index, and sleepiness comparison between FABP7.T61M carriers and noncarriers.
    • table S2. Health status comparison between FABP7.T61M carriers and noncarriers.
    • fig. S1. Baseline total sleep-wake time is not affected in Fabp7 KO mice.
    • fig. S2. Locomotor running wheel activity is not affected in Fabp7 KO mice.
    • fig. S3. REM sleep time is increased in Fabp7 KO mice during the recovery period following sleep deprivation.
    • fig. S4. Overexpression of FABP7.T61M mutation in astrocytes fragments wake only during the daytime in Drosophila.
    • fig. S5. Overexpression of FABP7.T61M mutation in astrocytes in male flies also fragments sleep.
    • fig. S6. Overexpression of FABP7.T61M mutation in astrocytes in male flies also fragments wake.
    • fig. S7. Conditional overexpression of FABP7.T61M mutation in glial cells of adult male flies also fragments sleep in Drosophila.

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