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Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment.
- Source :
-
Neuron . Jul2019, Vol. 103 Issue 2, p250-250. 1p. - Publication Year :
- 2019
-
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. • Methotrexate (MTX) causes a microglia-dependent reduction in Bdnf expression • Activity-regulated myelination requires Bdnf-TrkB signaling and fails after MTX • Conditional, inducible TrkB loss in OPCs impairs cognitive behavioral performance • TrkB agonism rescues cognitive performance after MTX only if OPCs express TrkB Methotrexate chemotherapy results in a microglial-dependent reduction of Bdnf expression and loss of activity-regulated myelination, which requires Bdnf to TrkB signaling. OPC-specific loss of TrkB results in cognitive impairment. Stimulating OPC TrkB signaling restores myelination and rescues cognition after MTX. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MYELINATION
*METHOTREXATE
*DISABILITIES
*COGNITIVE ability
Subjects
Details
- Language :
- English
- ISSN :
- 08966273
- Volume :
- 103
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Neuron
- Publication Type :
- Academic Journal
- Accession number :
- 137473329
- Full Text :
- https://doi.org/10.1016/j.neuron.2019.04.032