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Deficiency in short-chain fatty acid β-oxidation affects theta oscillations during sleep

Nature Genetics volume 34, pages 320–325 (2003)Cite this article

Abstract

In rodents, the electroencephalogram (EEG) during paradoxical sleep and exploratory behavior is characterized by theta oscillations. Here we show that a deficiency in short-chain acyl-coenzyme A dehydrogenase (encoded by Acads) in mice causes a marked slowing in theta frequency during paradoxical sleep only. We found Acads expression in brain regions involved in theta generation, notably the hippocampus. Microarray analysis of gene expression in mice with mutations in Acads indicates overexpression of Glo1 (encoding glyoxylase 1), a gene involved in the detoxification of metabolic by-products. Administration of acetyl-L-carnitine (ALCAR) to mutant mice significantly recovers slow theta and Glo1 overexpression. Thus, an underappreciated metabolic pathway involving fatty acid β-oxidation also regulates theta oscillations during sleep.

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Figure 1: Mapping of Tpf.
Figure 2: Expression pattern of Acads and Glo1.
Figure 3: Changes in gene expression in Acads mutant, wild-type and inbred mice.
Figure 4: Metabolic pathways involved in the activation of the glyoxylase system.

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Acknowledgements

We thank J. Vockley for providing the ACADS antibody; J. Garcia-Sevilla, M. Ferrer Alcon, C. Walzer and B. Pastori for help in immunoblot assays; P. Descombes, M. Docquier and O. Schaad for assistance in microarray and real-time RT–PCR analyses; A. Malafosse, N. Gregersen and S. Ghisla for discussions; and J. Flint and U. Schibler for critical reading of our first drafts. M.T. was supported by the Swiss National Science Foundation and the Geneva University Hospitals. P.A.W. and P.F. were supported by grants from the National Institutes of Health (the Center for Research Resources and the Heart, Lung, and Blood Institute, respectively). M.T. and P.F. were also supported by a grant from Roche Research Foundation.

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Authors and Affiliations

  1. Department of Psychiatry, Biochemistry and Genetics Unit, University of Geneva and Geneva University Hospitals, Chemin du Petit-Bel-Air 2, Chêne-Bourg, 1225, Switzerland

    Mehdi Tafti, Brice Petit, Didier Chollet & Elisabeth Neidhart

  2. Neuropsychiatry Division, Department of Psychiatry, Geneva University Hospitals, Chêne-Bourg, 1225, Switzerland

    Fabienne de Bilbao

  3. Department of Morphology, Centre Medical Universitaire, Geneva, 1211, Switzerland

    Jozsef Z Kiss

  4. Department of Genetics, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Philip A Wood

  5. Department of Biological Sciences, Stanford University, Stanford, 94305, California, USA

    Paul Franken

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Correspondence to Mehdi Tafti.

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Tafti, M., Petit, B., Chollet, D. et al. Deficiency in short-chain fatty acid β-oxidation affects theta oscillations during sleep. Nat Genet 34, 320–325 (2003). https://doi.org/10.1038/ng1174

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