CNS & Neurological Disorders - Drug Targets, 2012, 11, 000-000 1

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Current Understanding of the Interplay Between Catechol-O-Methyltransferase Genetic Variants, Sleep, Brain Development and Cognitive Performance in Schizophrenia Valter Tucci*,1, Glenda Lassi1 and Martien J. Kas*,2

1Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia. Via Morego, 30, 16131, Genoa, Italy 2Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience. University Medical Centre Utrecht. Universiteitsweg 100, 3584 CG Utrecht, The Netherlands

Abstract: Abnormal sleep is an endophenotype of schizophrenia. Here we provide an overview of the genetic mechanisms that link specific sleep physiological processes to schizophrenia-related cognitive defects. In particular, we will review the possible relationships between catechol-O-methyltransferase (COMT), sleep regulation and schizophrenia development. Recent studies validate the hypothesis that COMT mutations may trigger disturbances during adolescence that affect sleep and cortical development. Anomalies in cortical development during this critical developmental phase may increase the susceptibility for schizophrenia. In conclusion, in view of therapeutic efficacy, we can envisage indications for future investigations into the role of COMT for sleep regulation, cognitive performance and sleep-related cognitive deficits.

Keywords: COMT, sleep, cognition, brain development, Schizophrenia.

INTRODUCTION

The maturation, consolidation and decline of sleep and cognitive performance during life may involve common brain circuitries and molecular pathways [1-6]. The notion that a good night’s sleep improves mental health is accepted by the general public and has been supported by studies that show reduced cognitive performance following sleep deprivation [2, 7-9]. The interaction between sleep and cognitive abilities can be compromised by both environmental and genetic variables [10]. As an example of environmental pressure on sleep and cognitive performance, the ‘24/7’ attitude that dominates western society needs the support of an efficient cognitive performance and this can be achieved only by an appropriate functioning of the central nervous system (CNS). Since sleep is intimately associated with cognitive performance [2, 11], a fair question in neuroscience is to understand how CNS functioning is linked to sleep. Indeed, besides our own personal experiences, some of the most well-known industrial accidents of our recent times – Three Mile Island, Chernobyl, the Exxon Valdez – all occurred at night time or early morning, when operators with responsibilities were under the negative effects of sleep pressure. Furthermore, long-term sleep deprivation gives rise to a number of psychotic symptoms that, eventually, disappear after the recovery of sleep [9]. Moreover, sleep disturbances have been often reported in many psychiatric

*Address correspondence to these authors at the Department of Neuroscience and Brain technologies, Istituto Italiano di Tecnologia. Via Morego, 30, 16131, Genoa, Italy; Tel: 0039-010 71781747; Faxr: 0039-010 71781230; E-mail: valter.tucci@iit.it and Department of Neuroscience and Pharmaco-logy, Rudolf Magnus Institute of Neuroscience. University Medical Centre Utrecht. Universiteitsweg 100, 3584 CG Utrecht, The Netherlands; Tel: 0031-88-7568179; Fax: 0031-88-7569032; E-mail: m.j.h.kas@umcutrecht.nl

disorders such as, for example, schizophrenia [12-16]. The estimated cost to national health services for sleep and cognitive disorders is very high and a considerable co-morbidity between the two disorders is apparent in many clinical assessments. Although links between sleep and cognitive abilities are extensively reported in literature [17-25], the specific mechanisms that tie these two fundamental phenomena are still unclear but several hypotheses exist. As a consequence, one of the current challenges in neuroscience is to identify evolutionary advantages that promoted sleep and its role in neuronal functioning, cognitive processes and then mental health. These are complex issues in sleep biology that may be successfully addressed by use of effective experimental paradigms and well-chosen animal model systems. Sleep is commonly defined by well-defined changes in brain electrical activity and is considered an emerging property of neuronal networks in the brain [26, 27]. Besides theoretical, biological and evolutionary considerations on the relevance to investigate sleep-like states in single cells, electroencephalographic (EEG) and electromyographic technology made it possible to describe sleep-wake states which are characterized by specific brain waves and muscular activity levels. As a general concept, the amplitude and the frequency of these oscillations vary between at least three main states of life: wakefulness, non-REM (NREM) and REM (rapid-eye-movement) sleep states [11, 28-30]. Wakefulness is characterized by muscular activity, low-amplitude and high-frequency in the EEG; In NREM sleep we observe a relaxation of the muscular activity paralleled by a progressive increase in the EEG amplitude and by the presence of synchronized slow waves. Paradoxically, REM sleep presents an EEG similar to wakefulness but the activity of postural muscles is, instead, remarkably suppressed.

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We will review here the existing literature underscoring the relevance of sleep disturbances in relation to schizophrenia. Schizophrenia is a complex disease which is characterized by heterogeneity at the genetic and phenotypic levels. The goal of this special issue is to provide a broad understanding of the role of catechol-O-methyltransferase (COMT) in sleep, in schizophrenia and schizophrenia-related phenomena, such as reduced cognitive performance. Furthermore, recent studies of Maret and co-workers [31] corroborate the hypothesis that COMT mutations lead to sleep disturbances during early adolescence that subsequently affect cortical development. Altered cortical development during this critical stage may contribute to increased susceptibility for schizophrenia. Finally, we will conclude this review by discussing possibilities to reverse the consequences of COMT mutations on sleep, cognition and vigilance, taking into account individual variability in genetic background.

SLEEP DISTURBANCES IN SCHIZOPHRENIA

Schizophrenia is a serious psychiatric disorder that invalidates major cognitive abilities in affected patients. The presence of hallucinations and bizarre false beliefs, among other symptoms, has triggered in the past some tempting analogy to dreaming [32]. However, while both hallucinations and false beliefs occur during wakefulness, dreaming occurs only during sleep. The hypothesis that hallucinations were the product of REM episodes during wakefulness was then dismissed and REM sleep was concluded not to be abnormal in schizophrenic patients [32, 33]. Also other aspects related to rapid eye movements were investigated between patients and control subjects; however, no differences in REM sleep propensity were observed between schizophrenic patients and controls [34, 35] except for some associations between eye movements activity in REM and psychosis and emotional disturbances [36]. On the other hand, schizophrenia, as many other neurodevelopmental disorders with altered cognitive performance, presents dramatic sleep disturbances. Indeed, clinical reports on schizophrenia patients report poor quality of sleep that impairs quality of life [37]. Often, patients suffer of insomnia that ranges from a total sleeplessness to incapacity to fall asleep. Also, schizophrenic patients experience multiple awakenings, a degraded quality of physiological sleep, restless behaviours in bed and agitated sleep. According to commonly-recognized criteria for clinical diagnosis of disease (as for example DSM-IV), the sleep symptoms are considered related to the schizophrenia pathology if the patient experiences the disturbances for at least one month. In the case of insomnia, this will be associated with daytime fatigue or impaired daytime functioning [38]. These reports of sleep problems did not rely only on subjective evaluations of patients but were also reported on the basis of polysomnographic evaluations (e.g. [34, 39, 40]). Polysomnography consists in the monitoring of multiple electrophysiological parameters in subjects during sleep. Sleep disturbances have been often associated with the severity of the cognitive symptoms in schizophrenia. They may appear or precede the state of active psychosis [41-44]. The architecture of sleep in humans is different from other species. In particular, the overall sleep episode within a

circadian cycle of 24 hours is compacted in one long period of 7-8 hours that occurs during the night/dark phase of the day. This full-length episode with NREM-REM cycles starts with a scarce presence of REM episodes and as the subjective night continues the duration and the frequency of REMs increase dramatically. Several studies reported that the latency to the first REM episode in sleep is reduced in schizophrenic patients [34, 45-48]. This may be easily explained by a reduction of NREM sleep, the stage that precedes REM sleep. Indeed, a deficit of the slow wave sleep (SWS) (in the stage 4 of the NREM sleep) has been shown in schizophrenia [34, 46]. According to Feinberg [49] schizophrenia originates in adolescence because of a dysfunction that occurs in the maturational mechanism of synaptic elimination. This model suggests that schizophrenic patients exhibit an excessive synaptic pruning which, in turn, affects the synchronization of SWS. Interestingly, current experimental evidence indicates that sleep physiological oscillations and, in particular, SWS, are fundamental in cognitive processes that depend on sleep [50]. Cortical slow oscillations (<1 Hz) have been suggested as a physiological mechanism for the consolidation of memories during sleep. The current hypothesis states that the up- and down-states of this neuronal activity mediate the information processing between cortical and subcortical areas for a long-term storage of the memories (see [50] for an extensive review). Thus, it is likely that fundamental mechanisms which regulate SWS contribute to cognitive symptoms in schizophrenia. At the cognitive level, we can distinguish positive (e.g. hallucinations, delusions, disordered speech and thoughts) and negative (e.g. emotional and social disturbances) symptoms in schizophrenia. These categories correlate with specific effects in sleep. In particular, positive symptoms are accompanied by a significant presence of high frequency EEG episodes in sleep [36]. Negative symptoms are often associated with reduced REM latency and SWS deficits [44, 51, 52]. Several cognitive deficits correlate with SWS deficits, suggesting that a common mechanism in the prefrontal cortex (in which many slow wave oscillations originate) may underlie these disease features. For example, a recent study in human subjects has shown that slow waves, reflected in delta power during recovery sleep (following sleep deprivation), act to restore brain function, thereby improving cognitive performance that entails response inhibition. This study indicates that recovery sleep improved performance because of changes in brain function including prefrontal regions that resulted from delta rebound [53]. Furthermore, as sleep plays an important role in consolidation of procedural memory tasks, few studies have investigated this phenomenon in schizophrenic patients. In fact a deficit in the sleep-dependent consolidation processes for procedural tasks has been observed in schizophrenic patients [54] but as these patients were under medication it becomes difficult to exclude specific effects due to the treatment. Another link between SWS phenotype and schizophrenic pathology can be made on the basis of anatomical studies. For example, both schizophrenia and sleep deficits are often characterized by an increased ventricular space. For instance, by means of brain imaging techniques, specific SWS deficits have been associated to the abnormal ventricular

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morphology and functioning in schizophrenia [32, 44]. In particular, the total amount of sleep and the length of sleep episodes are inversely correlated with the volume of the third ventricle.

COMT, SLEEP, AND SCHIZOPHRENIA

The COMT enzyme, which is coded by the COMT gene, is responsible for the addition of a methyl group to catecholamines (e.g. dopamine etc.) and this process results in a degradation of dopamine. Dopamine exerts a main role in CNS functions such as movements and emotion/motivation, but it is also known to impact on the expression of sleep. Indeed, many neurological and psychiatric disorders that present an abnormal regulation of the level of dopamine in the brain are characterized by cognitive symptoms as well as sleep deficits. In addition, it has been shown that REM sleep potentiates the release of dopamine [55-57] and both clinical and experimental evidence have confirmed the role of dopamine in the modulation of sleep. It is known that the COMT gene is present in different variants (polymorphisms) which have been associated to specific roles in behavioural processes. Also, COMT polymorphisms are thought to cause general cognitive disorders such as those involved in schizophrenia due to the alteration of dopamine levels in the frontal lobe. Interestingly, by manipulating the levels of dopamine in mice, it is possible to promote or repress REM and NREM sleep [58]. In particular, increased levels of dopamine suppress REM-like states while decreased levels of dopamine mimic a novel SWS state in mice [58]. Early adolescence is a critical phase in life with respect to changes in sleep pattern [59], brain development [60], and sensitivity to psychiatric disease onset [61]. In schizophrenia, for example, cortical thinning and cognitive decline are important features of the disease that may be strongly influenced during this developmental stage (for a review see [62]). Interestingly, a recent study has shown that sleep and wakefulness are important modulators of cortical development as they can contribute to the increase and decrease of cortical spines, respectively [31]. Factors that contribute to disturbances in sleep/wakefulness during this sensitive phase may, therefore, play an important role in cortical development and possible to the subsequent cognitive decline, as observed in schizophrenia. COMT is potentially a relevant player in this process of decline in cortical development and cognitive performance. As described above, COMT is an enzyme that degrades catecholamines such as dopamine, epinephrine, and norepinephrine. Via their modulating effects on a wide variety of vital processes, such as metabolism, blood pressure and aggression [63-65], catecholamines can be important (in)direct mediators of sleep/wakefulness. For this reason, genetic alternations in COMT may influence sleep/wakefulness via impaired levels of catecholamine degradation. These effects on sleep/wakefulness during adolescence may lead to changes in density of cortical spines. Alternatively, COMT may have a direct influence on cortical development [66-69]. For example, a recent study provided the first longitudinal evidence to link a genetic

variant in COMT impacting DA signaling to structural cortical deficits in children with schizophrenia as well as in their non-psychotic siblings [70]. In addition, another study showed that COMT genotype was associated with structural differences in the right superior temporal sulcus and inferior prefrontal sulcus, where individuals carrying the Met158 allele had a thicker cortex with respect to their Val158 counterparts [66]. Interestingly, cognitive performance is also influenced by this mutation; however, the COMT genotype effects are dependent on gender and interact with puberty [71]. These effects may be related to dopamine levels, as COMT mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex [63].

COMT AND THE PHARMACOGENETICS OF SLEEP

The efficacy of modafinil has been associated to a specific variant (Val158Met) of the COMT gene [72]. Modafinil is a wake-promoting stimulant that may enhance primarily dopaminergic neurotransmission and is widely used in the treatment of narcolepsy (a sleep disorder characterized by excessive daytime sleep and cataplexy). A significant effect of modafinil to specific EEG frequencies has been reported according to the COMT genotype [72]. In particular, modafinil increases EEG activity in the Val/Val genotype while it has no particular effect on the Met/Met genotype in human subjects (Fig. 1). It is also known to promote cognitive performance in healthy subjects [73-76]. Modafinil promotes wakefulness and cognitive performance by increasing dopaminergic neurotransmission in specific brain areas, such as the prefrontal cortex [73]. In the study of Bonnet and colleagues [73], the authors subjected healthy volunteer subjects, subdivided for two genotypes (Val/Val and Met/Met), to an EEG assessment following sub-ministration of modafinil or caffeine. Caffeine is known for its role in repressing the effects of the endogenous sleep promoter adenosine in the basal forebrain [77]. Interestingly, modafinil treatment attenuated sleepiness in all subjects regardless of genotypes; however, differently from caffeine, it enhanced slow wave sleep in subjects with the Val/Val variant during recovery. This suggests also a differential impact of dopamine in sleep homeostasis with respect to, for example, adenosine. In addition, the Val/Val polymorphism influences the antidepressant effect that follows sleep deprivation [78]. As sleep pattern changes during early adolescence may potentially lead to mental illness due to changes in cortical development around this critical phase, early intervention to circumvent sleep disturbances may be an important step to take into consideration. COMT polymorphisms have been implicated in sleep disturbances associated with attention deficit/hyperactivity disorder (ADHD) [79] but also in young healthy men [80]. In ADHD, COMT Val allele carriers have poorer sleep continuity compared with children with the Met/Met genotype. This was observed both while receiving a placebo and while receiving methylphenidate treatment [79]. In healthy young men, the COMT Val158Met polymorphism predicted stable and frequency-specific inter-individual variations in brain α-oscillations. For example, the α-peak frequency in wakefulness was 1.4 Hz slower in men with the Val/Val genotype than in men with the Met/Met genotype.

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Moreover, Val/Val allele carriers exhibited less 11–13 Hz activity than Met/Met homozygotes in wakefulness, REM sleep, and NREM sleep. This genotype difference in brain α-oscillations was resistant to the effects of sleep deprivation and modafinil [80]. Thus, COMT polymorphisms have differential effects on sleep patterns in ADHD and healthy young men. Furthermore, modafinil treatment is not able to affect these genotype effects on brain α-oscillations in healthy young men. At this stage, it is not clear why modafinil has no effect on the genotype difference (Val/Val versus Met/Met) in brain α-oscillations. The most plausible explanation is that this genotype difference in brain α-oscillations is not related to dopamine signalling.

Fig. (1). Electroencephalographic activity following modafinil treatment. Top panel: percentage of electroencephalographic power (power density) after modafinil treatment respect to placebo (the 100% dashed line) in Val/Val compared Met/Met genotype. Bottom panel: F-values of genotype x treatment condition. The figure has been kindly provided by Prof. Hans-Peter Landolt [71].

As COMT catalyzes the breakdown of cerebral dopamine, modafinil is likely to be effective in individuals with sleep disturbances (e.g., due to COMT polymorphisms). However, a recent study reported that modafinil and the Val158Met polymorphism did not affect sleep homeostasis in recovery sleep (following sleep deprivation). In contrast to its negative effects on sleep, modafinil potently improves vigor and well-being, and maintains the baseline performance with respect to executive functioning and vigilant attention throughout sleep deprivation in Val/Val genotype subjects but is hardly effective in subjects with the Met/Met genotype [81]. This suggests a selective treatment effect of modafinil on vigilance following sleep deprivation that depends on the COMT genotype. In light of intervention during early adolescence, studies on the efficacy of the long-acting COMT inhibitor, tolcapone, on sleep quality may be of relevance. An observational study provides first evidence that tolcapone improves sleep quality and reduces daytime sleepiness in patients suffering from advanced Parkinson’s disease [82]. In view of selecting tolcapone as potential treatment, it is

important to consider its cytotoxicity as this turns out to be dependent on tolcapone dosage and to correlate with COMT Val/Met genotypes [83, 84]. These are important factors to consider before prescribing tolcapone as a sleep-promoting drug. To possibly circumvent these cytotoxic effects, these studies suggest that, in relation to cortical neurons, membrane-bound COMT-specific inhibitors can be developed and that tolcapone may be less hazardous at low doses and in specific genetic backgrounds [84].

CONCLUSIONS

We have reviewed recent studies that highlight the relation between sleep phenotypes and schizophrenia. Sleep abnormalities may represent an endophenotype of schizophrenia and cognitive processes depend on a good sleep physiology. However, the relationship between sleep and schizophrenia is complex and involves several molecular and circuitry pathways that need further study. Dopamine signalling may play a pivotal role in both sleep irregularities and schizophrenia. Furthermore, as developmental factors are important for the maturation of physiological and cognitive processes, specific neurodevelopmental stages may be critical for studying the interrelationship between sleep, brain development, and progressive cognitive decline (a core feature of schizophrenia). During adolescence, neuronal changes represent a critical process that has to be considered in relation to sleep [31] and to the susceptibility of developing a psychiatric disorder, such as schizophrenia. The deterioration of sleep during adolescence (e.g. due to social factors) has been associated with important physiological and educational negative consequences [85, 86]. In light of this, it is interesting to note that a longitudinal study is currently on-going to monitor age-related changes in NREM/REM sleep. This longitudinal study started in 9-year-old children and goes on throughout puberty [49, 87, 88]. Translational research (in mice and humans) will be critical to understand the functional interplay between genetic background (polymorphisms), environment, brain development and cognitive performance in order to contribute to the development of personalized and age-dependent treatment strategies.

ACKNOWLEDGMENTS

V.T. was supported by the European Commission FP7 Programme under project 223263 (PhenoScale).

ABBREVIATIONS

ADHD = Attention deficit/hyperactivity disorder CNS = Central nervous system COMT = Catechol-O-methyl transferase EEG = Electroencephalography NREM = Non-REM REM = Rapid eye movement SES = Slow wave sleep

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Received: December 23, 2011 Revised: January 19, 2012 Accepted: January 24, 2012