This is a really interesting study, which should stimulate new thinking and experimentation. cAMP-dependent signaling is a core component of the mammalian circadian pacemaker (O'Neill et al., 2008). Do those schizophrenic (and indeed non-schizophrenic) patients with sleep disorder show direct evidence for altered PDE4 signaling? If so, does genetic variation in the DISC1-PDE4 complex contribute to this and indicate a differential molecular diagnosis? Clapcote et al. (2007) reported differential effects of Disc1 missense mutations Q31L and L100P on brain PDE4 activity and on behavioral response to rolipram. Do these strains and indeed other Disc1 mutant mice have disturbed sleep patterns?

References:

O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science . 2008 May 16 ; 320(5878):949-53. Abstract

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron . 2007 May 3 ; 54(3):387-402. Abstract

View all comments by David J. Porteous

Although disturbed sleep is a prominent feature of schizophrenia that has been recognized since Kraepelin (1919), its relation to the pathophysiology, signs, and symptoms of schizophrenia remains poorly understood. In healthy individuals, there is now overwhelming evidence that critical aspects of learning and memory consolidation depend on sleep. Yet, in spite of the ubiquity of sleep disorders in schizophrenia, they have generally been overlooked as a potential contributor to cognitive deficits. As recently reviewed by Manoach and Stickgold (2009), an emerging literature suggests that abnormal sleep in schizophrenia may contribute to these cognitive deficits through its impairment of sleep-dependent memory consolidation.

The finding by Vecsey et al. that sleep deprivation leads to an increase in transcription and translation of the gene coding for phosphodiesterase-4 (PDE4), and that inhibiting the action of PDE4 with the drug rolipram restores both normal cAMP levels and sleep-dependent memory consolidation in rodents,...  Read more

Although disturbed sleep is a prominent feature of schizophrenia that has been recognized since Kraepelin (1919), its relation to the pathophysiology, signs, and symptoms of schizophrenia remains poorly understood. In healthy individuals, there is now overwhelming evidence that critical aspects of learning and memory consolidation depend on sleep. Yet, in spite of the ubiquity of sleep disorders in schizophrenia, they have generally been overlooked as a potential contributor to cognitive deficits. As recently reviewed by Manoach and Stickgold (2009), an emerging literature suggests that abnormal sleep in schizophrenia may contribute to these cognitive deficits through its impairment of sleep-dependent memory consolidation.

The finding by Vecsey et al. that sleep deprivation leads to an increase in transcription and translation of the gene coding for phosphodiesterase-4 (PDE4), and that inhibiting the action of PDE4 with the drug rolipram restores both normal cAMP levels and sleep-dependent memory consolidation in rodents, raises the question of whether rolipram could also restore sleep-dependent memory consolidation in individuals with schizophrenia. Manoach and her colleagues have published a pair of papers (Manoach et al., 2004; 2009) demonstrating that while schizophrenia patients show normal learning of a finger tapping motor sequence task (MST) during an initial training session, they fail to show the significant increase in speed that reliably develops across a night of sleep in healthy individuals (Walker et al., 2002). In these papers, they suggest that the failure of overnight consolidation may be related to a deficit in sleep spindles (Ferrarelli et al., 2007; Manoach et al., 2009), a characteristic EEG signature of non-REM sleep, which have been proposed to mediate memory consolidation in general (Sejnowski and Destexhe, 2000), and which have been shown to correlate with overnight improvement on the MST in particular (Nishida and Walker, 2007).

But the new findings of Vecsey et al. suggest another possibility, namely an overactive PDE4 system in schizophrenia. As others have noted here, some PDE4 isoforms bind to the normal form of the schizophrenia susceptibility gene DISC1, forming an inactive DISC1-PDE4 complex. If this inactivation fails in schizophrenia, then the normal sleep-dependent suppression of PDE4 activity may similarly fail, as PDE4 activity remains at inappropriately high levels. In other words, the failure of sleep-dependent memory consolidation in schizophrenia reported by Manoach et al. (2004, 2009) may be a consequence of the disrupted regulation of PDE4.

The experimental test of this hypothesis is quite simple and straightforward: Administration of rolipram, after initial MST training but prior to sleep (along with a possible second dose later in the night), should restore normal sleep-dependent enhancement of MST performance.

References:

Ferrarelli F, Huber R, Peterson MJ, Massimini M, Murphy M, Riedner BA, Watson A, Bria P, Tononi G. Reduced sleep spindle activity in schizophrenia patients. Am J Psychiatry. 2007;164(3):483-92. Abstract

Kraepelin E. Dementia praecox and paraphrenia (R. Barclay, Trans.). 1919. Edinburgh, Scotland: ES Livingston.

Manoach DS, Thakkar KN, Stroynowski E, Ely A, McKinley SK, Wamsley E, Djonlagic I, Vangel MG, Goff DC, Stickgold R. Reduced overnight consolidation of procedural learning in chronic medicated schizophrenia is related to specific sleep stages. J Psychiatr Res. 2009 Aug 7. Abstract

Manoach DS, Cain MS, Vangel MG, Khurana A, Goff DC, Stickgold R. A failure of sleep-dependent procedural learning in chronic, medicated schizophrenia. Biol Psychiatry. 2004;56:951-6. Abstract

Manoach DS, Stickgold R. Does abnormal sleep impair memory consolidation in schizophrenia? Front Hum Neurosci. 2009;3:21. Abstract

Nishida M, Walker MP. Daytime naps, motor memory consolidation and regionally specific sleep spindles. PLoS ONE. 2007;2(4):e341. Abstract

Sejnowski TJ, Destexhe A. Why do we sleep? Brain Res. 2000;886(1-2): 208-23. Abstract

Walker MP, Brakefield T, Morgan A, Hobson JA, Stickgold R. Practice with sleep makes perfect: sleep-dependent motor skill learning. Neuron. 2002;35(1):205-11. Abstract

The relationship between DISC1 and neuropsychiatric disorders, including schizophrenia, schizoaffective disorder, and bipolar disorder, has now been observed in several studies. Moreover, a number of studies have demonstrated that DISC1 appears to impact neurocognitive function. Nevertheless, the molecular mechanisms by which DISC1 could contribute to impaired CNS function are unclear, and these two papers shed light on this critical issue.

Millar et al. (2005) have followed the same strategy that they so successfully utilized in their initial DISC1 studies, identifying a translocation that associated with a psychotic illness. In contrast to DISC1, in which a pedigree was identified with a number of translocation carriers, this manuscript is based upon the identification of a single translocation carrier, who appears to manifest classic signs of schizophrenia, without evidence of mood dysregulation. Two genes are disrupted by this translocation: cadherin 8 and phosphodiesterase 4B (PDE4B). The...  Read more

The relationship between DISC1 and neuropsychiatric disorders, including schizophrenia, schizoaffective disorder, and bipolar disorder, has now been observed in several studies. Moreover, a number of studies have demonstrated that DISC1 appears to impact neurocognitive function. Nevertheless, the molecular mechanisms by which DISC1 could contribute to impaired CNS function are unclear, and these two papers shed light on this critical issue.

Millar et al. (2005) have followed the same strategy that they so successfully utilized in their initial DISC1 studies, identifying a translocation that associated with a psychotic illness. In contrast to DISC1, in which a pedigree was identified with a number of translocation carriers, this manuscript is based upon the identification of a single translocation carrier, who appears to manifest classic signs of schizophrenia, without evidence of mood dysregulation. Two genes are disrupted by this translocation: cadherin 8 and phosphodiesterase 4B (PDE4B). The researchers' elegant set of experiments provides compelling biological evidence that PDE4B interacts with DISC1 and suggests a mechanism mediated by cAMP for DISC1/PDE4B effects on basic molecular processes underlying learning, memory, and perhaps psychosis. It remains possible that PDE4B (and DISC1) are proteins fundamentally involved in cognitive processes, and that the observed relationship to psychotic illnesses represents a final common pathway of neurocognitive impairment. This would be consistent with data from our group (Lencz et al., in press) demonstrating that verbal memory impairment specifically predicts onset of psychosis in at-risk subjects. Similarly, Burdick et al. (2005) found that our DISC1 risk genotypes (Hodgkinson et al., 2004) were associated with impaired verbal working memory. Finally, Callicott et al. (2005) found that a DISC1 risk SNP, Ser704Cys, predicted hippocampal dysfunction, an SNP which we (DeRosse et al., unpublished data) have also found to link with the primary psychotic symptoms (persecutory delusions) manifested by the patient in the Millar et al. study. This body of evidence supports the notion that these proteins play fundamental roles in the key clinical manifestations of schizophrenia.

Kamiya et al. (2005) provide another potential mechanism for these effects, suggesting that a DISC1 mutation may disrupt cerebral cortical development, hinting that studies examining the role of DISC1 genotypes on brain structure and function in the at-risk schizophrenia pediatric patients may be fruitful.

Taken together, these papers add considerable new data suggesting that DISC1 plays a key role in the etiology of schizophrenia, and places DISC1 at the forefront of the rapidly growing body of schizophrenia candidate genes.

References:
Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16(12):1399-1402. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005; 102(24): 8627-8632. Abstract

Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK. Disrupted in Schizophrenia (DISC1): Association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75:862-872. Abstract

Lencz T, Smith CW, McLaughlin D, Auther A, Nakayama E, Hovey L, Cornblatt BA. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry (in press).

This study describes an interesting genetic link between PDE4B (phosphodiesterase 4B) and schizophrenia that may be related to a physical interaction with DISC1 (disrupted in schizophrenia 1), another gene associated with the psychiatric disorder. The study is highly suggestive of a role for the PDE4B/DISC1 complex in schizophrenia. However, the mechanistic model suggested by the authors whereby DISC1 sequesters PDE4B in an inactive state seems overly speculative, given the results presented in this paper and in prior studies that have examined the regulation of PDE4B by phosphorylation in the absence of DISC1.

View all comments by Angus Nairn