Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing <script type="math/tex">p75^{NTR}</script> up-regulation and astrocyte-mediated inflammation

Miguez, Andrés; García-Díaz Barriga, Gerardo; Brito, Verónica; Straccia, Marco; Giralt, Albert; Ginés, Silvia; Canals, Josep M.; Alberch, Jordi

doi:10.1093/HMG/DDV218

Title

Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing $p75^{NTR}$ up-regulation and astrocyte-mediated inflammation

Author

Miguez, Andrés

García-Díaz Barriga, Gerardo

Brito, Verónica

Straccia, Marco

Giralt, Albert

Ginés, Silvia

Canals, Josep M.

Alberch, Jordi

Abstract

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by motor and cognitive impairments, involving striatum, cortex and hippocampus. Synaptic and memory dysfunction in HD mouse models have been related to low levels of brain-derived neurotrophic factor (BDNF) and imbalance between TrkB and p75NTR receptors. In addition, astrocyte over-activation has also been suggested to contribute to HD cognitive deficits. Fingolimod (FTY720), a modulator of sphingosine-1 phosphate (S1P) receptors, has been shown to increase BDNF levels and to reduce astrogliosis, proving its potential to regulate trophic support and inflammatory response. In this view, we have investigated whether FTY720 improves synaptic plasticity and memory in the R6/1 mouse model of HD, through regulation of BDNF signaling and astroglial reactivity. Chronic administration of FTY720 from pre-symptomatic stages ameliorated long-term memory deficits and dendritic spine loss in CA1 hippocampal neurons from R6/1 mice. Furthermore, FTY720 delivery prevented astrogliosis and over-activation of nuclear factor kappa beta (NF-κB) signaling in the R6/1 hippocampus, reducing tumor necrosis factor alpha (TNFα) and induced nitric oxide synthase (iNOS) levels. TNFα decrease correlated with the normalization of p75NTR expression in the hippocampus of FTY720-treated R6/1 mice, thus preventing p75NTR/TrkB imbalance. In addition, FTY720 increased cAMP levels and promoted phosphorylation of CREB and RhoA in the hippocampus of R6/1 mice, further supporting its role in the enhancement of synaptic plasticity. Our findings provide new insights into the mechanism of action of FTY720 and reveal a novel therapeutic strategy to treat memory deficits in HD.

Language

English

Source (journal)

Human molecular genetics. - Oxford

Publication

Oxford : 2015

ISSN

0964-6906

DOI

10.1093/HMG/DDV218

Volume/pages

24 :17 (2015) , p. 4958-4970