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Objective  While abnormalities in myelin in tuberous sclerosis complex ( TSC ) have been known for some time, recent imaging‐based data suggest myelin abnormalities may be independent of the pathognomonic cortical lesions (“tubers”). Multiple mouse models of  TSC  exhibit myelination deficits, though the cell types responsible and the mechanisms underlying the myelin abnormalities remain unclear.    Methods  To determine the role of alterations in  mTOR  signaling in myelination, we generated a conditional knockout ( CKO ) mouse model using Cre‐recombinase and the  Olig2  promoter to inactivate the  Tsc2  gene in oligodendrocyte precursor cells.    Results  Characterization of myelin and myelin constituent proteins demonstrated a marked hypomyelination phenotype. Diffusion‐based magnetic resonance imaging studies were likewise consistent with hypomyelination. Hypomyelination was due in part to decreased myelinated axon density and myelin thickness as well as decreased oligodendrocyte numbers. Coincident with hypomyelination, an extensive gliosis was seen in both the cortex and white matter tracks, suggesting alterations in cell fate due to changes in  mTOR  activity in oligodendrocyte precursors. Despite a high‐frequency appendicular tremor and altered gait in  CKO  mice, no significant changes in activity, vocalizations, or anxiety‐like phenotypes were seen.    Interpretation  Our findings support a known role of  mTOR  signaling in regulation of myelination and demonstrate that increased  mTORC 1 activity early in development within oligodendrocytes results in hypomyelination and not hypermyelination. Our data further support a dissociation between decreased Akt activity and increased  mTORC 1 activity toward hypomyelination. Thus, therapies promoting activation of Akt‐dependent pathways while reducing  mTORC 1 activity may prove beneficial in treatment of human disease.

Hypomyelination following deletion of Tsc2 in oligodendrocyte precursors