Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment.

Affiliation

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: [Email]

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.

Keywords

BDNF,TrkB,adaptive myelination,chemotherapy-related cognitive impairment,myelin,myelin plasticity,oligodendrocyte,oligodendrocyte precursor cell,

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