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Dysregulated Cholinergic Signaling Inhibits Oligodendrocyte Maturation Following Demyelination.
Ravichandar, Roopa; Gadelkarim, Farah; Muthaiah, Rupadevi; Glynos, Nicolas; Murlanova, Kateryna; Rai, Nagendra K; Saraswat, Darpan; Polanco, Jessie J; Dutta, Ranjan; Pal, Dinesh; Sim, Fraser J.
Afiliación
  • Ravichandar R; Neuroscience Program, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
  • Gadelkarim F; Neuroscience Program, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
  • Muthaiah R; Department of Pharmacology and Toxicology, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
  • Glynos N; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
  • Murlanova K; Department of Physiology and Biophysics, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
  • Rai NK; Department of Neuroscience, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195.
  • Saraswat D; Department of Pharmacology and Toxicology, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
  • Polanco JJ; Neuroscience Program, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203.
  • Dutta R; Department of Neuroscience, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195.
  • Pal D; Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109.
  • Sim FJ; Neuroscience Program, Jacob's School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203 fjsim@buffalo.edu.
J Neurosci ; 44(28)2024 Jul 10.
Article en En | MEDLINE | ID: mdl-38749703
ABSTRACT
Dysregulation of oligodendrocyte progenitor cell (OPC) recruitment and oligodendrocyte differentiation contribute to failure of remyelination in human demyelinating diseases such as multiple sclerosis (MS). Deletion of muscarinic receptor enhances OPC differentiation and remyelination. However, the role of ligand-dependent signaling versus constitutive receptor activation is unknown. We hypothesized that dysregulated acetylcholine (ACh) release upon demyelination contributes to ligand-mediated activation hindering myelin repair. Following chronic cuprizone (CPZ)-induced demyelination (male and female mice), we observed a 2.5-fold increase in ACh concentration. This increase in ACh concentration could be attributed to increased ACh synthesis or decreased acetylcholinesterase-/butyrylcholinesterase (BChE)-mediated degradation. Using choline acetyltransferase (ChAT) reporter mice, we identified increased ChAT-GFP expression following both lysolecithin and CPZ demyelination. ChAT-GFP expression was upregulated in a subset of injured and uninjured axons following intraspinal lysolecithin-induced demyelination. In CPZ-demyelinated corpus callosum, ChAT-GFP was observed in Gfap+ astrocytes and axons indicating the potential for neuronal and astrocytic ACh release. BChE expression was significantly decreased in the corpus callosum following CPZ demyelination. This decrease was due to the loss of myelinating oligodendrocytes which were the primary source of BChE. To determine the role of ligand-mediated muscarinic signaling following lysolecithin injection, we administered neostigmine, a cholinesterase inhibitor, to artificially raise ACh. We identified a dose-dependent decrease in mature oligodendrocyte density with no effect on OPC recruitment. Together, these results support a functional role of ligand-mediated activation of muscarinic receptors following demyelination and suggest that dysregulation of ACh homeostasis directly contributes to failure of remyelination in MS.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Oligodendroglía / Enfermedades Desmielinizantes Límite: Animals Idioma: En Revista: J Neurosci Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Oligodendroglía / Enfermedades Desmielinizantes Límite: Animals Idioma: En Revista: J Neurosci Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos