Disrupted Circadian Rhythms in a Mouse Model of Schizophrenia

Sleep and circadian rhythm disruption has been widely observed in neuropsychiatric disorders including schizophrenia [1] and often precedes related symptoms [2]. However, mechanistic basis for this association remains unknown. Therefore, we investigated the circadian phenotype of blind-drunk (Bdr), a mouse model of synaptosomal-associated protein (Snap)-25 exocytotic disruption that displays schizophrenic endophenotypes modulated by prenatal factors and reversible by antipsychotic treatment [3, 4]. Notably, SNAP-25 has been implicated in schizophrenia from genetic [5–8], pathological [9–13], and functional studies [14–16]. We show here that the rest and activity rhythms of Bdr mice are phase advanced and fragmented under a light/dark cycle, reminiscent of the disturbed sleep patterns observed in schizophrenia. Retinal inputs appear normal in mutants, and clock gene rhythms within the suprachiasmatic nucleus (SCN) are normally phased both in vitro and in vivo. However, the 24 hr rhythms of arginine vasopressin within the SCN and plasma corticosterone are both markedly phase advanced in Bdr mice. We suggest that the Bdr circadian phenotype arises from a disruption of synaptic connectivity within the SCN that alters critical output signals. Collectively, our data provide a link between disruption of circadian activity cycles and synaptic dysfunction in a model of neuropsychiatric disease

Circadian Expression of Adiponectin and Its Receptors in Human Adipose Tissue

Adiponectin is one of the most clinically relevant cytokines associated with obesity. However, circadian rhythmicity of adiponectin in human adipose tissue (AT) has not been analyzed. To assess whether the mRNA levels of adiponectin and its receptors (ADIPOR1 and ADIPOR2) might show daily circadian rhythms in visceral and sc fat explants obtained from morbid obese women, visceral and sc abdominal AT biopsies (n = 6) were obtained from morbidly obese women (body mass index ≥40 kg/m2). Anthropometric variables were measured and fasting plasma glucose, lipid, and lipoprotein concentrations were analyzed. To investigate rhythmic expression pattern, AT explants were cultured during 24 h, and gene expression was analyzed at the following times: 0800, 1400, 2000, and 0200 h, using quantitative real-time PCR. All genes investigated showed a circadian rhythmicity and oscillated accurately and independently of the suprachiasmatic nucleus in both AT explants (P < 0.05). Adiponectin gene expression fluctuated in the same phase as its receptors. Correlation analyses between the genetic circadian oscillation and components of the metabolic syndrome revealed that adiposity and abdominal obesity correlated with a decrease in adiponectin and adiponectin receptors ADIPOR1 and ADIPOR2 amplitude (P < 0.05). Visceral fat showed a trend toward a phase delay and dampening of the mRNA amplitude of adiponectin as compared with sc fat. The mRNA expression of adiponectin and its receptors showed 24-h rhythmicity in human AT from morbidly obese patients