Sphingosine-1-phosphate receptor inhibition prevents denervation-induced dendritic atrophy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-03-31

AUTHORS

Laurent M. Willems, Nadine Zahn, Nerea Ferreirós, Klaus Scholich, Nicola Maggio, Thomas Deller, Andreas Vlachos

ABSTRACT

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. More... »

PAGES

28

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s40478-016-0303-x

DOI

http://dx.doi.org/10.1186/s40478-016-0303-x

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https://app.dimensions.ai/details/publication/pub.1010866369

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27036416


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85 length
86 lesion-induced changes
87 levels
88 live-cell microscopy
89 loss
90 major neurological diseases
91 microscopy
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93 mouse dentate granule cells
94 net reduction
95 network
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97 neuronal cell death
98 neurons
99 neuroprotective effects
100 novel neuroprotective effects
101 organotypic entorhino-hippocampal slice cultures
102 pathology
103 pathway
104 pharmaceuticals
105 primary pathology
106 profound changes
107 receptor signaling
108 recovery
109 reduction
110 region
111 results
112 retraction events
113 role
114 secondary injury
115 segments
116 set
117 signaling
118 slice cultures
119 stability
120 symptoms
121 target
122 total dendritic length
123 transneuronal effects
124 weeks
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