title: Mice lacking the circadian modulators SHARP1 and SHARP2 display altered sleep and mixed state endophenotypes of psychiatric disorders.
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.
authors.affiliation: Department of Neurology, University of Kiel, Kiel, Germany; Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Baier
authors.affiliation: Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Brzózka
authors.affiliation: Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Shahmoradi
authors.affiliation: Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Reinecke
authors.affiliation: Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Kroos
authors.affiliation: Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany.
authors.forename: Sven P
authors.initials: SP
authors.lastname: Wichert
authors.affiliation: Circadian Rhythms Group, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany; Medical Department I, University of Lübeck, Lübeck, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Oster
authors.affiliation: Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wehr
authors.affiliation: Department of Physiology, National University of Singapore, Singapore, Singapore.
authors.forename: Reshma
authors.initials: R
authors.lastname: Taneja
authors.affiliation: Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Göttingen, Germany; Carl-Ludwig Institute of Physiology, University of Leipzig, Leipzig, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hirrlinger
authors.affiliation: Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany; Research Group Gene Expression, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Moritz J
authors.initials: MJ
authors.lastname: Rossner
mesh_terms: D000818:Animals; D001007:Anxiety / Q000150:complications / Q000503:physiopathology; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use; D058068:Endophenotypes / Q000378:metabolism*; D005106:Exploratory Behavior / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D008297:Male; D001523:Mental Disorders / Q000150:complications / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D065808:Prepulse Inhibition / Q000187:drug effects; D012097:Repressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014851:Wakefulness / Q000187:drug effects / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003024:Clozapine; D012097:Repressor Proteins; D014157:Transcription Factors; C470968:Bhlhb3 protein, mouse; C485778:Hey2 protein, mouse