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Abnormal Wake/Sleep Pattern in a Novel Gain-Of-Function Model of DISC1

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Abnormal Wake/Sleep Pattern in a Novel Gain-Of-Function Model of DISC1

Hanna Jaaro-Peled et al. Neurosci Res.

Abstract

Sleep disturbances are common in psychiatric disorders, but the causal relationship between the two and the underlying genetic factors is unclear. The DISC1 gene is strongly linked to mood disorders and schizophrenia in a Scottish pedigree. In an earlier study we found a sleep homeostasis disturbance in a Drosophila model overexpressing wild-type human DISC1. Here we aimed to explore the relationship between sleep and the DISC1 gene in a mammalian model, a novel transgenic mouse model expressing full-length human DISC1. We assessed circadian rhythms by monitoring wheel running activity under normal 24-h light:dark conditions and in constant darkness and found the DISC1 mice to have normal circadian photoentrainment and normal intrinsic circadian period. We also assessed sleep duration and quality in the DISC1 mice and found that they were awake longer than wild-type controls at baseline with a tendency for lower rebound of delta activity during recovery from a short sleep deprivation. Thus we suggest that DISC1 may be involved in sleep regulation.

Keywords: Behavior; Circadian rhythms; DISC1; Mouse model; Non rapid eye movement sleep; Rapid eye movement sleep; Sleep homeostasis.

Conflict of interest statement

statement. None declared.

Figures

Figure 1
Figure 1. Generation of a transgenic model expressing full-length human DISC1 under control of the αCaMKII-promoter
(A) Transgene construct: cDNA of full-length human DISC1 was inserted into a modified pMM403 vector under the αCaMKII promoter and a FLAG tag. (B) DISC1 transgene mRNA expression was assessed by RT-PCR. It was expressed in olfactory bulbs (OB), frontal cortex (FC), hippocampus (Hc), and basal ganglia (BG), but not in the cerebellum (Cb). (C) DISC1 transgene protein expression was confirmed by immunoprecipitation with FLAG followed by immunoblot with DISC1 antibodies.
Figure 2
Figure 2. The DISC1 mice show normal circadian activity
(A) Example actograms over 55 days of wheel running activity are shown for WT and DISC1 mice (x-axis: time in hours; y-axis: days). Days 25–40 animals were housed under a 12 h light: 12 h dark cycle. The remainder of the experiment was in constant darkness to measure the intrinsic circadian period of the animals and phase shift light pulses were give on day 65. (B) The mean wheel counts during 12 h light: 12 h dark cycle indicates similar activity onset, offset and behavior, except lower activity of the DISC1 mice during dark phase (interaction F143,1430=3.18, ***p<0.0001). (C) Circadian period measured during constant darkness is not different between the groups. (D) The response to a phase shift light pulse (day 65) also does not differ between groups.
Figure 3
Figure 3. DISC1 mice show abnormal wake/sleep patterns
(A) DISC1 mice show abnormal distribution of wakefulness and sleep. (left panels, Baseline) The hourly distribution of wakefulness, NREM sleep and REM sleep during baseline was significantly affected in DISC1 mice (interaction F23,322 ≥ 1.9, p ≤ 0.02). Significant genotype differences (p < 0.05) at specific hours are highlighted by red symbols. (right panels, Recovery) Following 2 h of sleep deprivation (SD, indicated by black rectangles), DISC1 mice no longer significantly differ from WT mice in the distribution or amount of wakefulness and NREM sleep (interaction F23,207 < 0.7, p > 0.6). DISC1 mice show a tendency for decreased REM sleep during the light period compared to WT (interaction F23,207 = 1.7, p = 0.07), similar to baseline. White background indicates light periods, and grey background indicates dark periods. (B) DISC1 mice show nonsignificant changes in the time course of delta activity during NREM sleep. (left panel) The time course of delta activity during baseline showed a tendency to be affected by genotype (interaction F17,221 = 1.9, p = 0.08), with DISC1 mice tending to have a higher amplitude of day-night variations. White background indicates the light period, and grey background the dark period. (right panel) The time course of delta activity during recovery after 2 h of sleep deprivation (SD, black rectangle) did not differ between genotypes (interaction F10,80 = 1.2, p = 0.3), but DISC1 mice tended to show a decreased overall delta level compared to WT during recovery (genotype effect F1,8 = 3.7, p = 0.09).
Figure 4
Figure 4. Behavioral characterization of the DISC1 mice
(A) DISC1 mice did not differ from WT littermates in locomotion over 2 h (left, p=0.16) and % center activity during the first 5 min (right, p=0.56) in a novel open field. (B) DISC1 mice did not differ from WT mice in activity (left, p=0.45) or short term memory (right, p=0.11) as assessed by spontaneous alternations in the Y-maze. (C) DISC1 mice showed normal startle response (left, p=0.30) and prepulse inhibition [right, F(1,10)=0.70, p=0.42]. (D) DISC1 mice did not differ from WT mice in the % immobility during the 4 last minutes of the forced swim test (p=0.91). (E) Although DISC1 mice froze normally in the trained context after fear conditioning, they froze less in an altered context (p<0.05) resulting in higher context specific freezing (p<0.001).

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