title: Reduced Sleep Spindles in Schizophrenia: A Treatable Endophenotype That Links Risk Genes to Impaired Cognition?
abstract: Although schizophrenia (SZ) is defined by waking phenomena, abnormal sleep is a common feature. In particular, there is accumulating evidence of a sleep spindle deficit. Sleep spindles, a defining thalamocortical oscillation of non-rapid eye movement stage 2 sleep, correlate with IQ and are thought to promote long-term potentiation and enhance memory consolidation. We review evidence that reduced spindle activity in SZ is an endophenotype that impairs sleep-dependent memory consolidation, contributes to symptoms, and is a novel treatment biomarker. Studies showing that spindles can be pharmacologically enhanced in SZ and that increasing spindles improves memory in healthy individuals suggest that treating spindle deficits in patients with SZ may improve cognition. Spindle activity is highly heritable, and recent large-scale genome-wide association studies have identified SZ risk genes that may contribute to spindle deficits and illuminate their mechanisms. For example, the SZ risk gene CACNA1I encodes a calcium channel that is abundantly expressed in the thalamic spindle generator and plays a critical role in spindle activity based on a mouse knockout. Future genetic studies of animals and humans can delineate the role of this and other genes in spindles. Such cross-disciplinary research, by forging empirical links in causal chains from risk genes to proteins and cellular functions to endophenotypes, cognitive impairments, symptoms, and diagnosis, has the potential to advance the mechanistic understanding, treatment, and prevention of SZ. This review highlights the importance of deficient sleep-dependent memory consolidation among the cognitive deficits of SZ and implicates reduced sleep spindles as a potentially treatable mechanism.
authors.affiliation: Department of Psychiatry and Psychiatric and Neurodevelopmental Genetics Unit, Analytic, Boston; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts. Electronic address: dara@nmr.mgh.harvard.edu.
authors.forename: Dara S
authors.initials: DS
authors.lastname: Manoach
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Jen Q
authors.initials: JQ
authors.lastname: Pan
authors.affiliation: Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Stickgold
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D058068:Endophenotypes; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D000069077:Memory Consolidation / Q000502:physiology; D012559:Schizophrenia / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D007319:Sleep Initiation and Maintenance Disorders / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D012894:Sleep Stages / Q000235:genetics / Q000502:physiology*
keywords: Cognition; Endophenotype; Genetics; Memory; Schizophrenia; Sleep; Spindles