Methamphetamine decreases dentate gyrus stem cell self-renewal and shifts the differentiation towards neuronal fate

Sofia Baptista; Charlène Lasgi; Caroline Benstaali; Nuno Milhazes; Fernanda Borges; Carlos Fontes-Ribeiro; Fabienne Agasse; Ana Paula Silva

doi:10.1016/j.scr.2014.08.003

Methamphetamine decreases dentate gyrus stem cell self-renewal and shifts the differentiation towards neuronal fate

Stem Cell Res. 2014 Sep;13(2):329-41. doi: 10.1016/j.scr.2014.08.003. Epub 2014 Aug 13.

Authors

Sofia Baptista¹, Charlène Lasgi², Caroline Benstaali², Nuno Milhazes³, Fernanda Borges⁴, Carlos Fontes-Ribeiro¹, Fabienne Agasse⁵, Ana Paula Silva⁶

Affiliations

¹ 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.
² Institut Curie, Orsay, France.
³ 3CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal; Institute of Health Sciences-North, Gandra, Portugal.
⁴ 3CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
⁵ Institut Curie, Orsay, France; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
⁶ 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.

PMID: 25201326
DOI: 10.1016/j.scr.2014.08.003

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Cell Cycle Checkpoints / drug effects
Cell Death / drug effects
Cell Proliferation / drug effects*
Cells, Cultured
Central Nervous System Stimulants / toxicity*
Cyclin E / metabolism
Dentate Gyrus / drug effects*
Dentate Gyrus / metabolism
Dentate Gyrus / pathology
Doublecortin Domain Proteins
Doublecortin Protein
ErbB Receptors / metabolism
Excitatory Amino Acid Antagonists / pharmacology
Methamphetamine / toxicity*
Mice, Inbred C57BL
Microtubule-Associated Proteins / metabolism
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
N-Methylaspartate / metabolism
Neural Stem Cells / drug effects*
Neural Stem Cells / metabolism
Neural Stem Cells / pathology
Neurogenesis / drug effects*
Neurons / drug effects*
Neurons / metabolism
Neurons / pathology
Neuropeptides / metabolism
Phosphorylation
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate / metabolism
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Signal Transduction / drug effects
Time Factors

Substances

Central Nervous System Stimulants
Cyclin E
Dcx protein, mouse
Doublecortin Domain Proteins
Doublecortin Protein
Excitatory Amino Acid Antagonists
Microtubule-Associated Proteins
Neuropeptides
Receptors, N-Methyl-D-Aspartate
SOXB1 Transcription Factors
Sox2 protein, mouse
Methamphetamine
N-Methylaspartate
EGFR protein, mouse
ErbB Receptors
Mapk1 protein, mouse
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3