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Collaboration between TrkB and mTOR pathways during remyelination in a cuprizone mouse model
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Caruso, Danielle V.. Collaboration between TrkB and mTOR pathways during remyelination in a cuprizone mouse model. Retrieved from https://doi.org/doi:10.7282/t3-70qf-5a91

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TitleCollaboration between TrkB and mTOR pathways during remyelination in a cuprizone mouse model
NameCaruso, Danielle V. (author); Dreyfus, Cheryl (chair); Wood, Teresa (member); Zhou, Renping (member); James, Morgan (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-10 (degree)
SubjectNeurosciences, Toxicology, Cuprizone, mTOR, Remyelination, TrkB
Extent1 online resource (77 pages) : illustrations
DescriptionA central question in demyelinating diseases is how to reverse these conditions and prevent relapse of the disease. In the last several years, the Dreyfus laboratory has made many discoveries to bring us closer to understanding some of the mechanisms involved in remyelination. Previous studies have found that endogenous brain derived neurotrophic factor (BDNF) expression promotes oligodendrocyte cell survival and proliferation in a demyelinated lesion. BDNF’s mechanism of action involves binding to its high-affinity receptor, the tyrosine kinase receptor B (TrkB) on oligodendrocytes, which signals downstream activators of the MAPK/Erk pathway to promote myelination. To study the effects of the TrkB receptor more closely, the Dreyfus lab used tamoxifen inducible Trkb knockdown mice in a cuprizone model of demyelination to measure myelin protein expression in the corpus callosum. After 6 weeks of cuprizone, the mice had significant loss of myeline proteins, including myelin basic protein (MBP) and myelin-associated glycoprotein (MAG). The mice were then given normal food for two weeks after cuprizone diet (6+2-weeks). This 6+2-week remyelination phase also demonstrated significant loss of myelin proteins when compared to their control counterparts. The lab then allowed the mice to feed on control chow for 4-weeks post-cuprizone (6+4-weeks), in which they observed a recovery in the expression of myelin proteins. Our lab found that there was a dramatic loss in the percent of myelinated axons at 6- and 6+2-week timepoints. However, these deficits were rescued by 6+4-weeks. Although it may seem that TrkB plays an initial role in the expression of myelin proteins and percent of myelinated of axons, our lab did not observe changes in myelin thickness, measured by g-ratio analysis.

Coinciding with these studies, our collaborator, Dr. Teresa Wood and her laboratory study a similar pathway involved in oligodendrocyte lineage cell differentiation, the mTOR pathway. The Wood lab had studied that conditional knockout of Mtor from NG2 cells, a mature oligodendrocyte precursor cell (OPC), demonstrated a significant decrease in g-ratios of mice fed cuprizone for 6-weeks compared to control fed mice. These deficits persisted in 6+2-weeks but were reversed by 6+4-weeks. In contrast to what the Dreyfus lab had found, there was no difference in the percent of myelinated axons among the mice at any timepoint.

It is seen that without one of the two pathways there is recovery in myelin integrity by 4-weeks of remyelination. Taken together, these studies support my hypothesis that the TrkB/MAPK/Erk and Akt/mTOR signaling pathways interact during demyelinating and remyelinating lesions and the loss of one pathway is compensated by the other.

To determine whether one pathway compensates for the other during remyelination after cuprizone-induced demyelination, I used a double knockout mouse model that has both Trkb and Mtor conditionally knocked down under the control of the Plp promoter in oligodendrocytes. The mice were fed 0.2% cuprizone pellets for 6-weeks and then removed from cuprizone and given control food for 4-weeks to allow for remyelination. Corpora callosa were dissected and lysed for western blot analysis for myelin proteins. The results demonstrated that double knockout mice had a significant loss of proteolipid protein (PLP) and MAG proteins when compared to their control counterparts. The single knockout TrkB (TrkB-KO) mice and the single knockout mTOR (mTOR-KO) mice did not demonstrate any changes in myelin proteins at 6+4-weeks compared to their controls. These results suggest that both the TrkB and mTOR pathways are required for myelin protein synthesis in a remyelinating lesion.

To further investigate the effects that these two pathways have on remyelination, I used my double knockout and TrkB-KO mouse models to perform electron microscopy after 6+4-weeks cuprizone treatment. The results showed a decrease in the percent of myelinated axons in the double knockout mice compared to their controls. The TrkB-KO mice did not show any changes in the percent of myelinated axons compared to controls. These data demonstrate that loss of both pathways leads to a disruption in the ability to generate new myelinated axons at 6+4-weeks.

In conclusion, these studies demonstrate that the TrkB and mTOR pathways are involved in remyelination in the corpus callosum and that they may interact downstream their signaling pathways to aid in the production and utilization of myelin proteins, as well as the generation of new myelinated axons.
NoteM.S.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-70qf-5a91
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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