Abstract
Mice lacking a functional Biogenesis of Lysosome-related Organelles Complex 1 (BLOC-1), such as those of the pallid line, display cognitive and behavioural impairments reminiscent of those presented by individuals with intellectual and developmental disabilities. Although disturbances in the sleep/wake cycle are commonly lamented by these individuals, the underlying mechanisms, including the possible role of the circadian timing system, are still unknown. In this paper, we have explored sleep/circadian malfunctions and underlying mechanisms in BLOC-1-deficient pallid mice. These mutants exhibited less sleep behaviour in the beginning of the resting phase than wild-type mice with a more broken sleeping pattern in normal light-dark conditions. Furthermore, the strength of the activity rhythms in the mutants were reduced with significantly more fragmentation and lower precision than in age-matched controls. These symptoms were accompanied by an abnormal preference for the open arm in the elevated plus maze in the day and poor performance in the novel object recognition at night. At the level of the central circadian clock (the suprachiasmatic nucleus, SCN), loss of BLOC-1 caused subtle morphological changes including a larger SCN and increased expression of the relative levels of the clock gene Per2 product during the day but did not affect the neuronal activity rhythms. In the hippocampus, the pallid mice presented with anomalies in the cytoarchitecture of the Dentate Gyrus granule cells, but not in CA1 pyramidal neurones, along with altered PER2 protein levels as well as reduced pCREB/tCREB ratio during the day. Our findings suggest that lack of BLOC-1 in mice disrupts the sleep/wake cycle and performance in behavioural tests associated with specific alterations in cytoarchitecture and protein expression.
Highlights
Biogenesis of Lysosome-related Organelles Complex 1 (BLOC-1) (Biogenesis of Lysosome-related Organelles Complex-1) is a ubiquitously expressed, stable octameric protein complex containing, among other subunits, dysbindin and pallidin
The number of sleep bouts did not vary between genotypes (Figure 1C), their averaged duration was significantly shorter in pallid mice than in WT during the day (Figure 1D and Table 1)
To examine the possibility that loss of functional BLOC-1 altered the cellular organisation of the suprachiasmatic nucleus (SCN), which might be causal to the observed sleep and circadian abnormalities, we examined the gross morphology of the SCN in Nissl-stained sections
Summary
BLOC-1 (Biogenesis of Lysosome-related Organelles Complex-1) is a ubiquitously expressed, stable octameric protein complex containing, among other subunits, dysbindin and pallidin (reviewed by Ghiani and Dell’Angelica, 2011; Mullin et al, 2011). Advances have been made in unravelling the function of this protein complex in the biogenesis of lysosome-related organelles and, at least, BLOC-1 Deficiency Affects Sleep Timing of a subset of recycling endosomes (Di Pietro et al, 2006; Setty et al, 2007; Newell-Litwa et al, 2010; Delevoye et al, 2016; reviewed by Dell’Angelica, 2016; Hartwig et al, 2018). Drosophila melanogaster lacking functional BLOC-1 display impaired neurotransmission and altered behaviour (Cheli et al, 2010; Shao et al, 2011; Dickman et al, 2012; Mullin et al, 2015; Chen et al, 2017) These findings support the proposed argument that mutations affecting BLOC-1 stability elicit cognitive and behavioural deficits. A 6-year-old male has been identified as BLOC-1-deficient (due to a mutation in the dysbindin-encoding gene) and presenting with the symptoms of HPS as well as with motor and language developmental delays (Bryan et al, 2017), and a 52-year-old female has been described as deficient in the same complex (due to a mutation in the pallidin-encoding gene) and presenting with HPS together with schizophrenia (Okamura et al, 2018)
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