1. Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment.
- Author
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Geraghty AC, Gibson EM, Ghanem RA, Greene JJ, Ocampo A, Goldstein AK, Ni L, Yang T, Marton RM, Paşca SP, Greenberg ME, Longo FM, and Monje M
- Subjects
- Animals, Brain-Derived Neurotrophic Factor genetics, Brain-Derived Neurotrophic Factor metabolism, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Channelrhodopsins genetics, Channelrhodopsins metabolism, Cognition Disorders genetics, Disease Models, Animal, Humans, Luminescent Proteins genetics, Luminescent Proteins metabolism, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath pathology, Myelin Sheath ultrastructure, Oligodendrocyte Precursor Cells drug effects, Organic Chemicals therapeutic use, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Recognition, Psychology drug effects, Signal Transduction drug effects, Signal Transduction genetics, Urea analogs & derivatives, Urea metabolism, Cognition Disorders drug therapy, Cognition Disorders pathology, Immunosuppressive Agents therapeutic use, Methotrexate therapeutic use, Myelin Sheath metabolism
- Abstract
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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