title: Sphingosine-1-phosphate receptor inhibition prevents denervation-induced dendritic atrophy.
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.
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany.
authors.forename: Laurent M
authors.initials: LM
authors.lastname: Willems
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Zahn
authors.affiliation: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, ZAFES, Goethe-University Frankfurt, Frankfurt, 60590, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, ZAFES, Goethe-University Frankfurt, Frankfurt, 60590, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.affiliation: Talpiot Medical Leadership Program, Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, 52621, Israel.|Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel.
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggio
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany. Andreas.Vlachos@med.uni-duesseldorf.de.|Present Address: Institute for Anatomy II, Faculty of Medicine, Heinrich-Heine-University, Duesseldorf, 40225, Germany. Andreas.Vlachos@med.uni-duesseldorf.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vlachos
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects* / Q000473:pathology*; D003714:Denervation / Q000009:adverse effects; D018728:Entorhinal Cortex / Q000166:cytology / Q000293:injuries*; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*; D009924:Organ Culture Techniques; D019580:Perforant Pathway / Q000378:metabolism; D010768:Phosphoserine / Q000031:analogs & derivatives / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C111922:Cacybp protein, mouse; D002135:Calcium-Binding Proteins; D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid; C000611541:VPC23019; D010768:Phosphoserine; D000068876:Fingolimod Hydrochloride
keywords: Brain injury; Entorhinal cortex lesion; Lipid signaling; Multiple sclerosis; Neuroinflammation; Structural plasticity