title: Long-term consequences of chronic fluoxetine exposure on the expression of myelination-related genes in the rat hippocampus.
abstract: The selective serotonin reuptake inhibitor (SSRI) fluoxetine is widely prescribed for the treatment of symptoms related to a variety of psychiatric disorders. After chronic SSRI treatment, some symptoms remediate on the long term, but the underlying mechanisms are not yet well understood. Here we studied the long-term consequences (40 days after treatment) of chronic fluoxetine exposure on genome-wide gene expression. During the treatment period, we measured body weight; and 1 week after treatment, cessation behavior in an SSRI-sensitive anxiety test was assessed. Gene expression was assessed in hippocampal tissue of adult rats using transcriptome analysis and several differentially expressed genes were validated in independent samples. Gene ontology analysis showed that upregulated genes induced by chronic fluoxetine exposure were significantly enriched for genes involved in myelination. We also investigated the expression of myelination-related genes in adult rats exposed to fluoxetine at early life and found two myelination-related genes (Transferrin (Tf) and Ciliary neurotrophic factor (Cntf)) that were downregulated by chronic fluoxetine exposure. Cntf, a neurotrophic factor involved in myelination, showed regulation in opposite direction in the adult versus neonatally fluoxetine-exposed groups. Expression of myelination-related genes correlated negatively with anxiety-like behavior in both adult and neonatally fluoxetine-exposed rats. In conclusion, our data reveal that chronic fluoxetine exposure causes on the long-term changes in expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders.
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Human Genetics, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Kroeze
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Peeters
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, European Graduate School of Neuroscience, Maastricht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Boulle
authors.affiliation: Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
authors.forename: J L
authors.initials: JL
authors.lastname: Pawluski
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, European Graduate School of Neuroscience, Maastricht, The Netherlands.
authors.forename: D L A
authors.initials: DL
authors.lastname: van den Hove
authors.affiliation: Department of Human Genetics, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Human Genetics, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Molecular Developmental Biology, Faculty of Science, Radboud institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: J R
authors.initials: JR
authors.lastname: Homberg
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D020934:Ciliary Neurotrophic Factor / Q000235:genetics*; D005473:Fluoxetine / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D000069451:Long Term Adverse Effects / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects / Q000235:genetics; D010597:Pharmacogenetics; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014168:Transferrin / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D020934:Ciliary Neurotrophic Factor; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; D014168:Transferrin