Abstract
Sleep and/or circadian rhythm disruption (SCRD) is seen in up to 80% of schizophrenia patients. The co-morbidity of schizophrenia and SCRD may in part stem from dysfunction in common brain mechanisms, which include the glutamate system, and in particular, the group II metabotropic glutamate receptors mGlu2 and mGlu3 (encoded by the genes Grm2 and Grm3). These receptors are relevant to the pathophysiology and potential treatment of schizophrenia, and have also been implicated in sleep and circadian function. In the present study, we characterised the sleep and circadian rhythms of Grm2/3 double knockout (Grm2/3 -/-) mice, to provide further evidence for the involvement of group II metabotropic glutamate receptors in the regulation of sleep and circadian rhythms. We report several novel findings. Firstly, Grm2/3 -/- mice demonstrated a decrease in immobility-determined sleep time and an increase in immobility-determined sleep fragmentation. Secondly, Grm2/3 -/- mice showed heightened sensitivity to the circadian effects of light, manifested as increased period lengthening in constant light, and greater phase delays in response to nocturnal light pulses. Greater light-induced phase delays were also exhibited by wildtype C57Bl/6J mice following administration of the mGlu2/3 negative allosteric modulator RO4432717. These results confirm the involvement of group II metabotropic glutamate receptors in photic entrainment and sleep regulation pathways. Finally, the diurnal wheel-running rhythms of Grm2/3 -/- mice were perturbed under a standard light/dark cycle, but their diurnal rest-activity rhythms were unaltered in cages lacking running wheels, as determined with passive infrared motion detectors. Hence, when assessing the diurnal rest-activity rhythms of mice, the choice of assay can have a major bearing on the results obtained.
Highlights
Schizophrenia is a debilitating psychiatric disorder that affects 0.3–0.7% of the world’s population [1], while sleep and/or circadian rhythm disruption (SCRD) is observed in 30–80% of schizophrenia patients [2]
Relative to Grm2/3+/+ mice, total sleep time was markedly reduced in Grm2/3-/- mice (F1,21 = 6.456, P = 0.019; Fig 1A). This reduction in sleep time was driven by decreased light phase sleep (F1,22 = 18.107, P =
Dark phase sleep bouts were shorter in Grm2/3-/- than Grm2/3+/+ mice (F1,21 = 5.735, P = 0.026), the total number of dark phase sleep bouts was unaffected by genotype (F1,21 = 0.050, P = 0.825)
Summary
Schizophrenia is a debilitating psychiatric disorder that affects 0.3–0.7% of the world’s population [1], while sleep and/or circadian rhythm disruption (SCRD) is observed in 30–80% of schizophrenia patients [2]. Sleep disturbances in schizophrenia include increases in sleep latency and sleep fragmentation, and reductions in total sleep time, sleep efficiency, rapid eye movement (REM) sleep latency, REM sleep density and slow-wave sleep duration [2,3,4]. Typical circadian abnormalities in the disorder include the abnormal phasing, instability and fragmentation of rest-activity rhythms [5,6,7,8,9]. Some of these abnormalities may be secondary to the disorder and its drug treatment, but the co-morbidity of schizophrenia and SCRD may stem from dysfunction in common brain mechanisms (e.g. specific neurotransmitter systems) [10, 11]. Glutamate release in the prefrontal cortex displays rhythmic fluctuations during the sleep-wake cycle; it increases during wakefulness and REM sleep episodes, but decreases during non-REM sleep [23,24,25]
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