Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner
The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endog...
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MDPI AG
2020-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/9/3079 |
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| author | Abhisarika Patnaik Eleonora Spiombi Angelisa Frasca Nicoletta Landsberger Marta Zagrebelsky Martin Korte |
| author_facet | Abhisarika Patnaik Eleonora Spiombi Angelisa Frasca Nicoletta Landsberger Marta Zagrebelsky Martin Korte |
| author_sort | Abhisarika Patnaik |
| collection | DOAJ |
| description | The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from <i>Mecp2</i> and <i>Cdkl5</i> mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod. |
| first_indexed | 2024-03-10T20:12:56Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T20:12:56Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e79bc6895f0f4a77a4b72bbf72657a0f2023-11-19T22:50:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01219307910.3390/ijms21093079Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent MannerAbhisarika Patnaik0Eleonora Spiombi1Angelisa Frasca2Nicoletta Landsberger3Marta Zagrebelsky4Martin Korte5Zoological Institute, Division of Cellular Neurobiology, TU Braunschweig, D-38106 Braunschweig, GermanyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20100 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20100 Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, 20100 Milan, ItalyZoological Institute, Division of Cellular Neurobiology, TU Braunschweig, D-38106 Braunschweig, GermanyZoological Institute, Division of Cellular Neurobiology, TU Braunschweig, D-38106 Braunschweig, GermanyThe brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from <i>Mecp2</i> and <i>Cdkl5</i> mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.https://www.mdpi.com/1422-0067/21/9/3079FingolimodFTY720BDNFprimary culturesdendritesdendritic spines |
| spellingShingle | Abhisarika Patnaik Eleonora Spiombi Angelisa Frasca Nicoletta Landsberger Marta Zagrebelsky Martin Korte Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner International Journal of Molecular Sciences Fingolimod FTY720 BDNF primary cultures dendrites dendritic spines |
| title | Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner |
| title_full | Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner |
| title_fullStr | Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner |
| title_full_unstemmed | Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner |
| title_short | Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner |
| title_sort | fingolimod modulates dendritic architecture in a bdnf dependent manner |
| topic | Fingolimod FTY720 BDNF primary cultures dendrites dendritic spines |
| url | https://www.mdpi.com/1422-0067/21/9/3079 |
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