Schizophrenia Research Forum - A Catalyst for Creative Thinking


Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, Huang T, Brown KM, Li XY, Descalzi G, Kim SS, Chen T, Shang YZ, Zhuo M, Houslay MD, Abel T. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature. 2009 Oct 22 ; 461(7267):1122-5. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  David J. Porteous, SRF Advisor
Submitted 29 October 2009
Posted 30 October 2009
  I recommend the Primary Papers

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. PorteousComment by:  Robert Stickgold (Disclosure), Dara Manoach
Submitted 2 November 2009
Posted 3 November 2009
  I recommend the Primary Papers

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

View all comments by Robert Stickgold
View all comments by Dara Manoach