FTY720 (fingolimod), an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. We show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions. Sphk2-/- mice have lower levels of hippocampal sphingosine-1-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. Thus, sphingosine-1-phosphate and SphK2 play specific roles in memory functions and FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories.
Bibliographical noteFunding Information:
This work was supported by US National Institutes of Health (NIH) grant R37GM043880 to S.S. Behavioral studies were supported by 5P01DA009789 to A.H.L. and R21AG042745 to L.E.W. LTP studies were supported by R01NS057758 to T.M.R. The Lipidomics core was supported in part by NIH grant P30CA16059 to the Massey Cancer Center. Modeling studies were supported by National Natural Science Foundation of China grant 91029704 to C.L. We thank R. Proia (US National Institutes of Health) for providing the Sphk2−/− mice, B.L. Mason for technical assistance and S. Lima for discussions.