David Pritchett

Evaluating the links between schizophrenia and sleep and circadian rhythm disruption

Sleep and circadian rhythm disruption (SCRD) and schizophrenia are often co-morbid. Here, we propose that the co-morbidity of these disorders stems from the involvement of common brain mechanisms. We summarise recent clinical evidence that supports this hypothesis, including the observation that the treatment of SCRD leads to improvements in both the sleep quality and psychiatric symptoms of schizophrenia patients. Moreover, many SCRD-associated pathologies, such as impaired cognitive performance, are routinely observed in schizophrenia. We suggest that these associations can be explored at a mechanistic level by using animal models. Specifically, we predict that SCRD should be observed in schizophrenia-relevant mouse models. There is a rapidly accumulating body of evidence which supports this prediction, as summarised in this review. In light of these emerging data, we highlight other models which warrant investigation, and address the potential challenges associated with modelling schizophrenia and SCRD in rodents. Our view is that an understanding of the mechanistic overlap between SCRD and schizophrenia will ultimately lead to novel treatment approaches, which will not only ameliorate SCRD in schizophrenia patients, but also will improve their broader health problems and overall quality of life.

Genetic mouse models relevant to schizophrenia: taking stock and looking forward.

Genetic mouse models relevant to schizophrenia complement, and have to a large extent supplanted, pharmacological and lesion-based rat models. The main attraction is that they potentially have greater construct validity; however, they share the fundamental limitations of all animal models of psychiatric disorder, and must also be viewed in the context of the uncertain and complex genetic architecture of psychosis. Some of the key issues, including the choice of gene to target, the manner of its manipulation, gene-gene and gene-environment interactions, and phenotypic characterization, are briefly considered in this commentary, illustrated by the relevant papers reported in this special issue.

Deletion of Metabotropic Glutamate Receptors 2 and 3 (mGlu2 & mGlu3) in Mice Disrupts Sleep and Wheel-Running Activity, and Increases the Sensitivity of the Circadian System to Light

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.

d-amino acid oxidase knockout (Dao(-/-) ) mice show enhanced short-term memory performance and heightened anxiety, but no sleep or circadian rhythm disruption.

d‐amino acid oxidase (DAO, DAAO) is an enzyme that degrades d‐serine, the primary endogenous co‐agonist of the synaptic N‐methyl‐d‐aspartate receptor. Convergent evidence implicates DAO in the pathophysiology and potential treatment of schizophrenia. To better understand the functional role of DAO, we characterized the behaviour of the first genetically engineered Dao knockout (Dao−/−) mouse. Our primary objective was to assess both spatial and non‐spatial short‐term memory performance. Relative to wildtype (Dao+/+) littermate controls, Dao−/− mice demonstrated enhanced spatial recognition memory performance, improved odour recognition memory performance, and enhanced spontaneous alternation in the T‐maze. In addition, Dao−/− mice displayed increased anxiety‐like behaviour in five tests of approach/avoidance conflict: the open field test, elevated plus maze, successive alleys, light/dark box and novelty‐suppressed feeding. Despite evidence of a reciprocal relationship between anxiety and sleep and circadian function in rodents, we found no evidence of sleep or circadian rhythm disruption in Dao−/− mice. Overall, our observations are consistent with, and extend, findings in the natural mutant ddY/Dao− line. These data add to a growing body of preclinical evidence linking the inhibition, inactivation or deletion of DAO with enhanced cognitive performance. Our results have implications for the development of DAO inhibitors as therapeutic agents.

Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders: what makes a good homeostat?

All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well‐being. This is no less true for psychiatric well‐being than for physical well‐being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well‐being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis.

Implicit processing of tactile information: Evidence from the tactile change detection paradigm

People can maintain accurate representations of visual changes without necessarily being aware of them. Here, we investigate whether a similar phenomenon (implicit change detection) also exists in touch. In Experiments 1 and 2, participants detected the presence of a change between two consecutively-presented tactile displays. Tactile change blindness was observed, with participants failing to report the presence of tactile change. Critically, however, when participants had to make a forced choice response regarding the number of stimuli presented in the two displays, their performance was significantly better than chance (i.e., implicit change detection was observed). Experiment 3 demonstrated that tactile change detection does not necessarily involve a shift of spatial attention toward the location of change, regardless of whether the change is explicitly detected. We conclude that tactile change detection likely results from comparing representations of the two displays, rather than by directing spatial attention to the location of the change.

Searching for cognitive enhancement in the Morris water maze: better and worse performance in D‐amino acid oxidase knockout (Dao−/−) mice

A common strategy when searching for cognitive‐enhancing drugs has been to target the N‐methyl‐d‐aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D‐amino acid oxidase (DAO) degrades neutral D‐amino acids such as D‐serine, the primary endogenous co‐agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long‐term potentiation and facilitated water maze acquisition of ddY/Dao− mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao−/−) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao−/− mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao−/− mice exhibited normal performance in two alternative assays of long‐term spatial memory: the appetitive and aversive Y‐maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long‐term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted.

Sleep and circadian rhythm disruption and recognition memory in schizophrenia.

Schizophrenia patients often show irregularities in sleep and circadian rhythms and deficits in recognition memory. Similar phenotypes are seen in schizophrenia-relevant genetic mouse models, such as synaptosomal associated protein of 25 kDa (Snap-25) point mutant mice, vasoactive intestinal peptide receptor 2 (Vipr2) knockout mice, and neuregulin 1 (Nrg1)-deficient mice. Sleep and circadian abnormalities and impaired recognition memory may be causally related in both schizophrenia patients and schizophrenia-relevant mouse models, since sleep deprivation, abnormal photic input, and the manipulation of core clock genes (cryptochrome 1/2) can all disrupt object recognition memory in rodent models. The recognition deficits observed in patients and mouse models (both schizophrenia-related and -unrelated) are discussed here in terms of the dual-process theory of recognition, which postulates that there are two recognition mechanisms-recollection versus familiarity-that can be selectively impaired by brain lesions, neuropsychiatric conditions, and putatively, sleep and circadian rhythm disruption. However, based on this view, the findings from patient studies and studies using genetic mouse models (Nrg1 deficiency) seem to be inconsistent with each other. Schizophrenia patients are impaired at recollection (and to a lesser extent, familiarity judgments), but Nrg1-deficient mice are impaired at familiarity-based object recognition, raising concerns regarding the validity of using these genetically modified mice to model recognition phenotypes observed in patients. This issue can be resolved in future animal studies by examining performance in different variants of the spontaneous recognition task-the standard, perirhinal cortex-dependent, object recognition task versus the hippocampus-dependent object-place recognition task-in order to see which of the two recognition mechanisms is more disrupted.

Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders: what makes a good homeostat?: What makes a good homeostat?

All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well‐being. This is no less true for psychiatric well‐being than for physical well‐being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well‐being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis.

What Makes a Good Homeostat? Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders

All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well‐being. This is no less true for psychiatric well‐being than for physical well‐being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well‐being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis.