title: Methamphetamine decreases dentate gyrus stem cell self-renewal and shifts the differentiation towards neuronal fate.
abstract: Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse that negatively interferes with neurogenesis. In fact, we have previously shown that METH triggers stem/progenitor cell death and decreases neuronal differentiation in the dentate gyrus (DG). Still, little is known regarding its effect on DG stem cell properties. Herein, we investigate the impact of METH on mice DG stem/progenitor cell self-renewal functions. METH (10nM) decreased DG stem cell self-renewal, while 1nM delayed cell cycle in the G0/G1-to-S phase transition and increased the number of quiescent cells (G0 phase), which correlated with a decrease in cyclin E, pEGFR and pERK1/2 protein levels. Importantly, both drug concentrations (1 or 10nM) did not induce cell death. In accordance with the impairment of self-renewal capacity, METH (10nM) decreased Sox2(+)/Sox2(+) while increased Sox2(-)/Sox2(-) pairs of daughter cells. This effect relied on N-methyl-d-aspartate (NMDA) signaling, which was prevented by the NMDA receptor antagonist, MK-801 (10μM). Moreover, METH (10nM) increased doublecortin (DCX) protein levels consistent with neuronal differentiation. In conclusion, METH alters DG stem cell properties by delaying cell cycle and decreasing self-renewal capacities, mechanisms that may contribute to DG neurogenesis impairment followed by cognitive deficits verified in METH consumers.
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Baptista
authors.affiliation: Institut Curie, Orsay, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Lasgi
authors.affiliation: Institut Curie, Orsay, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Benstaali
authors.affiliation: 3CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal; Institute of Health Sciences-North, Gandra, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Milhazes
authors.affiliation: 3CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fontes-Ribeiro
authors.affiliation: Institut Curie, Orsay, France; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Agasse
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: apmartins@fmed.uc.pt.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Silva
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D019927:Cyclin E / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D066246:ErbB Receptors / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008694:Methamphetamine / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D019927:Cyclin E; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018691:Excitatory Amino Acid Antagonists; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D016194:Receptors, N-Methyl-D-Aspartate; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D008694:Methamphetamine; D016202:N-Methylaspartate; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3