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Conditional Deletion of the L-Type Calcium Channel Cav1.2 in NG2-Positive Cells Impairs Remyelination in Mice.
Santiago González, Diara A; Cheli, Veronica T; Zamora, Norma N; Lama, Tenzing N; Spreuer, Vilma; Murphy, Geoffrey G; Paez, Pablo M.
Afiliação
  • Santiago González DA; Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203, and.
  • Cheli VT; Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203, and.
  • Zamora NN; Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203, and.
  • Lama TN; Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203, and.
  • Spreuer V; Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203, and.
  • Murphy GG; Molecular and Behavioral Neuroscience Institute, Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109.
  • Paez PM; Hunter James Kelly Research Institute, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, New York 14203, and ppaez@buffalo.edu.
J Neurosci ; 37(42): 10038-10051, 2017 10 18.
Article em En | MEDLINE | ID: mdl-28899915
ABSTRACT
Exploring the molecular mechanisms that drive the maturation of oligodendrocyte progenitor cells (OPCs) during the remyelination process is essential to developing new therapeutic tools to intervene in demyelinating diseases such as multiple sclerosis. To determine whether L-type voltage-gated calcium channels (L-VGCCs) are required for OPC development during remyelination, we generated an inducible conditional knock-out mouse in which the L-VGCC isoform Cav1.2 was deleted in NG2-positive OPCs (Cav1.2KO). Using the cuprizone (CPZ) model of demyelination and mice of either sex, we establish that Cav1.2 deletion in OPCs leads to less efficient remyelination of the adult brain. Specifically, Cav1.2KO OPCs mature slower and produce less myelin than control oligodendrocytes during the recovery period after CPZ intoxication. This reduced remyelination was accompanied by an important decline in the number of myelinating oligodendrocytes and in the rate of OPC proliferation. Furthermore, during the remyelination phase of the CPZ model, the corpus callosum of Cav1.2KO animals presented a significant decrease in the percentage of myelinated axons and a substantial increase in the mean g-ratio of myelinated axons compared with controls. In addition, in a mouse line in which the Cav1.2KO OPCs were identified by a Cre reporter, we establish that Cav1.2KO OPCs display a reduced maturational rate through the entire remyelination process. These results suggest that Ca2+ influx mediated by L-VGCCs in oligodendroglial cells is necessary for normal remyelination and is an essential Ca2+ channel for OPC maturation during the remyelination of the adult brain.SIGNIFICANCE STATEMENT Ion channels implicated in oligodendrocyte differentiation and maturation may induce positive signals for myelin recovery. Voltage-gated Ca2+ channels (VGCCs) are important for normal myelination by acting at several critical steps during oligodendrocyte progenitor cell (OPC) development. To determine whether voltage Ca2+ entry is involved in oligodendrocyte differentiation and remyelination, we used a conditional knockout mouse for VGCCs in OPCs. Our results indicate that VGCCs can modulate oligodendrocyte maturation in the demyelinated brain and suggest that voltage-gated Ca2+ influx in OPCs is critical for remyelination. These findings could lead to novel approaches for obtaining a better understanding of the factors that control OPC maturation in order to stimulate this pool of progenitors to replace myelin in demyelinating diseases.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteoglicanas / Deleção de Genes / Canais de Cálcio Tipo L / Bainha de Mielina / Antígenos / Fibras Nervosas Mielinizadas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Neurosci Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteoglicanas / Deleção de Genes / Canais de Cálcio Tipo L / Bainha de Mielina / Antígenos / Fibras Nervosas Mielinizadas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Neurosci Ano de publicação: 2017 Tipo de documento: Article