Many patients with Huntington's disease (HD) exhibit disturbances in their daily cycle of sleep and wake as part of their symptoms. These patients have difficulty sleeping at night and staying awake during the day, which has a profound impact on the quality of life of the patients and their care-givers. In the present study, we examined diurnal and circadian rhythms of four models of HD including the BACHD, CAG 140 knock-in and R6/2 CAG 140 and R6/2 CAG 250 lines of mice. The BACHD and both R6/2 lines showed profound circadian phenotypes as measured by wheel-running activity. Focusing on the BACHD line for further analysis, the amplitude of the rhythms in the BACHD mice declined progressively with age. In addition, the circadian regulation of heart rate and body temperature in freely behaving BACHD mice were also disrupted. Furthermore, the distribution of sleep as well as the autonomic regulation of heart rate was disrupted in this HD model. To better understand the mechanistic underpinnings of the circadian disruption, we used electrophysiological tools to record from neurons within the central clock in the suprachiasmatic nucleus (SCN). The BACHD mice exhibit reduced rhythms in spontaneous electrical activity in SCN neurons. Interestingly, the expression of the clock gene PERIOD2 was not altered in the SCN of the BACHD line. Together, this data is consistent with the hypothesis that the HD mutations interfere with the expression of robust circadian rhythms in behavior and physiology. The data raise the possibility that the electrical activity within the central clock itself may be altered in this disease.

In mammals, the circadian oscillators that drive daily behavioral and endocrine rhythms are located in the hypothalamic suprachiasmatic nucleus (SCN). While the SCN is anatomically well-situated to receive and transmit temporal cues to the rest of the brain and periphery, there are many holes in our understanding of how this temporal regulation occurs. Unanswered questions include how cell autonomous circadian oscillations within the SCN remain synchronized to each other as well as communicate temporal information to downstream targets. In recent years, it has become clear that neuropeptides are critically involved in circadian timekeeping. One such neuropeptide, vasoactive intestinal peptide (VIP), defines a cell population within the SCN and is likely used as a signaling molecule by these neurons. Converging lines of evidence suggest that the loss of VIP or its receptor has a major influence on the ability of the SCN neurons to generate circadian oscillations as well as synchronize these cellular oscillations. VIP, acting through the VPAC(2) receptor, exerts these effects in the SCN by activating intracellular signaling pathways and, consequently, modulating synaptic transmission and intrinsic membrane currents. Anatomical evidence suggests that these VIP expressing neurons connect both directly and indirectly to endocrine and other output targets. Striking similarities exist between the role of VIP in mammals and the role of Pigment Dispersing Factor (PDF), a functionally related neuropeptide, in the Drosophila circadian system. Work in both mammals and insects suggests that further research into neuropeptide function is necessary to understand how circadian oscillators work as a coordinated system to impose a temporal structure on physiological processes within the organism.

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Two overlapping and antiparallel genes on chromosome 1, Disrupted In Schizophrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) translocation which segregates with schizophrenia through at least four generations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetiology of major psychiatric illness. We have constructed a contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examination of the genomic structure of DISC1. The gene consists of thirteen exons, estimated to extend across at least 300 kb of DNA. The antisense gene DISC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DISC1 belongs to the rare AT-AC class of introns. We have also mapped marker DIS251 in close proximity to DISC1, localising the gene within a critical region identified by several independent studies. Information regarding the structure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated to carriers of the translocation. Molecular Psychiatry (2001) 6, 173-178.