Sleep/Wake Disruption in a Mouse Model of BLOC-1 Deficiency

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.

Melatonin treatment of repetitive behavioral deficits in the Cntnap2 mouse model of autism spectrum disorder

“…Structural analysis of the SCN was performed as previously described ( Lee et al, 2018 ). WT and Cntnap2 KO mice (males, 3–4 mo) were anesthetized with isoflurane at a specific time during the night (ZT 14) and transcardially perfused with phosphate buffered saline (PBS, 0.1 M, pH 7.4) containing 4% ( w / v ) paraformaldehyde (PFA, Electron Microscopy Sciences, Hatfield, PA).…”

Sex‐dimorphic effects of biogenesis of lysosome‐related organelles complex‐1 deficiency on mouse perinatal brain development

“…For Nissl Staining, coronal brain sections (20 μm) were stained with a 1% (w/v) cresyl violet (Sigma-Aldrich Corp., St. Louis, MO) solution as previously reported (Lee et al, 2018). Photographs were acquired on a Zeiss Axioskop equipped with a Zeiss color or monochrome Axiocam using the AxioVision software (Zeiss, Pleasanton, CA) and used to determine the thickness of the cerebral cortex (layers I-VI) in rostral and caudal sections, the outer border and total sectional area of the hippocampus, and the cell density and cytoarchitecture in the Cornu Ammonis (CA)1 subfield of the hippocampus.…”

“…Interestingly, a small subset of these studies has raised the notion of a putative role for BLOC-1 in mouse brain development. Thus, the levels of both pallidin and dysbindin have been found to be developmentally regulated in the rodent brain (Ghiani et al, 2010;Ito et al, 2010), and lack of BLOC-1 was found to partially impair neurite outgrowth and dendritic spine morphogenesis in vitro (Ghiani et al, 2010;Ito et al, 2010;Ma, Fei, Fu, Ren, & Wang, 2011) as well as neuronal arborization in vivo (Lee et al, 2018).…”

“…Notwithstanding that such proposed association has failed to reach genome-wide statistical significance (Farrell et al, 2015), it stirred an array of studies on possible roles of the dysbindin protein, on its own or as part of BLOC-1, in CNS functions (reviewed by Ghiani & Dell'Angelica, 2011;Hartwig et al, 2018;Mullin, Gokhale, Larimore, & Faundez, 2011;Wang, Xu, Lazarovici, & Zheng, 2017). These studies have led to the recognition that adult mice deficient in BLOC-1, with such deficiency being caused by homozygous mutations in either the dysbindin-or pallidin-encoding genes, display a variety of cognitive and behavioral abnormalities (reviewed by Ghiani & Dell'Angelica, 2011;Mullin et al, 2011;Talbot, 2009; see also Bhardwaj, Stojkovic, Kiessling, Srivastava, & Cermakian, 2015;Chang et al, 2018;Lee et al, 2018;Petit et al, 2017;Spiegel, Chiu, James, Jentsch, & Karlsgodt, 2015), even when such abnormalities have not been consistently observed among the very few patients reported to suffer from HPS due to mutations in the corresponding human genes (Badolato et al, 2012;Bastida et al, 2019;Bryan et al, 2017;Li et al, 2003;Lowe et al, 2013;Okamura et al, 2018;Yousaf et al, 2016). Interestingly, a small subset of these studies has raised the notion of a putative role for BLOC-1 in mouse brain development.…”

Potential Circadian Rhythms in Oligodendrocytes? Working Together Through Time

“…Arrows highlight OL coexpressing the markers. Mice were perfused at Zeitgeber Time (ZT) 6 and double-immunolabelling for O4 or CNPase and Per2 was performed as previously reported [50,51]. PER2 expression can be also appreciated in other neural cells surrounding the O4 positive OL.…”