Mice lacking the circadian modulators SHARP1 and SHARP2 display altered sleep and mixed state endophenotypes of psychiatric disorders

Paul C Baier; Magdalena M Brzózka; Ali Shahmoradi; Lisa Reinecke; Christina Kroos; Sven P Wichert; Henrik Oster; Michael C Wehr; Reshma Taneja; Johannes Hirrlinger; Moritz J Rossner

doi:10.1371/journal.pone.0110310

Mice lacking the circadian modulators SHARP1 and SHARP2 display altered sleep and mixed state endophenotypes of psychiatric disorders

PLoS One. 2014 Oct 23;9(10):e110310. doi: 10.1371/journal.pone.0110310. eCollection 2014.

Authors

Affiliations

¹ Department of Neurology, University of Kiel, Kiel, Germany; Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany.
² Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany.
³ Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
⁴ Circadian Rhythms Group, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany; Medical Department I, University of Lübeck, Lübeck, Germany.
⁵ Department of Physiology, National University of Singapore, Singapore, Singapore.
⁶ Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Göttingen, Germany; Carl-Ludwig Institute of Physiology, University of Leipzig, Leipzig, Germany.
⁷ Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany; Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

Abstract

Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anxiety / complications
Anxiety / physiopathology
Basic Helix-Loop-Helix Transcription Factors / deficiency*
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Circadian Rhythm / drug effects
Circadian Rhythm / physiology*
Clozapine / pharmacology
Clozapine / therapeutic use
Endophenotypes / metabolism*
Exploratory Behavior / drug effects
Gene Expression Profiling
Gene Expression Regulation / drug effects
Gene Regulatory Networks
Male
Mental Disorders / complications
Mental Disorders / physiopathology*
Mice, Inbred C57BL
Prepulse Inhibition / drug effects
Repressor Proteins / deficiency*
Repressor Proteins / genetics
Repressor Proteins / metabolism
Sleep / drug effects
Sleep / physiology*
Transcription Factors / deficiency*
Transcription Factors / genetics
Transcription Factors / metabolism
Wakefulness / drug effects
Wakefulness / genetics

Substances

Basic Helix-Loop-Helix Transcription Factors
Bhlhb3 protein, mouse
Hey2 protein, mouse
Repressor Proteins
Transcription Factors
Clozapine

Grants and funding

H. Oster is a Lichtenberg Fellow of the Volkswagen Foundation. This work was supported by the Deutsche Forschungsgemeinschaft (CMPB and grant Klinische Forschergruppe (KFO: RO 4076/1-1) 241). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.