Sphingosine-1-phosphate receptor inhibition prevents denervation-induced dendritic atrophy

A hallmark of several major neurological diseases is neuronal cell death. In addition to this primary pathology, secondary injury is seen in connected brain regions in which neurons not directly affected by the disease a
A hallmark of several major neurological diseases is neuronal cell death. In addition to this primary pathology, secondary injury is seen in connected brain regions in which neurons not directly affected by the disease are denervated. These transneuronal effects on the network contribute considerably to the clinical symptoms. Since denervated neurons are viable, they are attractive targets for intervention. Therefore, we studied the role of Sphingosine-1-phosphate (S1P)-receptor signaling, the target of Fingolimod (FTY720), in denervation-induced dendritic atrophy. The entorhinal denervation in vitro model was used to assess dendritic changes of denervated mouse dentate granule cells. Live-cell microscopy of GFP-expressing granule cells in organotypic entorhino-hippocampal slice cultures was employed to follow individual dendritic segments for up to 6 weeks after deafferentation. A set of slice cultures was treated with FTY720 or the S1P-receptor (S1PR) antagonist VPC23019. Lesion-induced changes in S1P (mass spectrometry) and S1PR-mRNA levels (laser microdissection and qPCR) were determined. Denervation caused profound changes in dendritic stability. Dendritic elongation and retraction events were markedly increased, resulting in a net reduction of total dendritic length (TDL) during the first 2 weeks after denervation, followed by a gradual recovery in TDL. These changes were accompanied by an increase in S1P and S1PR1- and S1PR3-mRNA levels, and were not observed in slice cultures treated with FTY720 or VPC23019. We conclude that inhibition of S1PR signaling prevents dendritic destabilization and denervation-induced dendrite loss. These results suggest a novel neuroprotective effect for pharmaceuticals targeting neural S1PR pathways.
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Metadaten
Author:Laurent Maximilian Willems, Nadine Zahn, Nerea Ferreirós Bouzas, Klaus Scholich, Nicola Maggio, Thomas Deller, Andreas Vlachos
URN:urn:nbn:de:hebis:30:3-306310
DOI:http://dx.doi.org/10.1186/s40478-016-0303-x
ISSN:2051-5960
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27036416
Parent Title (English):Acta Neuropathologica Communications
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2016/03/31
Date of first Publication:2016/03/31
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/06/14
Tag:Brain injury; Entorhinal cortex lesion; Lipid signaling; Multiple sclerosis; Neuroinflammation; Structural plasticity
Volume:4
Issue:28
Pagenumber:12
HeBIS PPN:399783911
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License Logo Veröffentlichungsvertrag für Publikationen

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