TY  - JOUR
A1  - Willems, Laurent Maximilian
A1  - Zahn, Nadine
A1  - Ferreirós Bouzas, Nerea
A1  - Scholich, Klaus
A1  - Maggio, Nicola
A1  - Deller, Thomas
A1  - Vlachos, Andreas
T1  - Sphingosine-1-phosphate receptor inhibition prevents denervation-induced dendritic atrophy
T2  - Acta Neuropathologica Communications
N2  - 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.
KW  - Brain injury
KW  - Entorhinal cortex lesion
KW  - Lipid signaling
KW  - Multiple sclerosis
KW  - Neuroinflammation
KW  - Structural plasticity
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/30631
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-306310
SN  - 2051-5960
VL  - 4
IS  - 28
PB  - BioMed Central
CY  - London
ER  -