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Updated: Apr 29, 2026
Extinction Training During the Reconsolidation Window Prevents Recovery of Fear
Published on: August 24, 2012
Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory
Nitai C Hait1, Laura E Wise2, Jeremy C Allegood3
11] Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [2] Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. [3].
Abstract:
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.
Insights
Fingolimod (FTY720) works in the brain by inhibiting histone deacetylases (HDACs) to improve memory and learning. This mechanism is independent of its immune effects and may help treat memory deficits.
Area of Science:
- Neuroscience
- Pharmacology
- Epigenetics
Background:
- Fingolimod (FTY720) is an FDA-approved multiple sclerosis drug with incompletely understood central nervous system (CNS) benefits.
- These CNS effects appear independent of its known immunomodulatory actions.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying FTY720's beneficial CNS effects.
- To investigate the role of sphingosine kinase 2 (SphK2) and histone deacetylases (HDACs) in FTY720's action on memory.
Main Methods:
- Investigated FTY720 phosphorylation and nuclear localization.
- Assessed HDAC inhibition and histone acetylation changes.
- Utilized Sphk2 knockout mice to study memory functions.
Main Results:
- FTY720 is phosphorylated by SphK2 in the nucleus, inhibiting HDACs and increasing histone acetylation.
- FTY720 enhances memory and learning-associated gene expression in the brain, rescuing memory deficits.
- Sphk2 knockout mice exhibit memory deficits and reduced histone acetylation.
Conclusions:
- SphK2 and its downstream effects on HDACs are critical for memory function.
- FTY720's HDAC inhibitory action in the brain offers a novel therapeutic avenue for memory disorders.
- FTY720 may serve as an adjuvant therapy for facilitating the extinction of aversive memories.
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