title: Fibroblast growth factor 23 signaling in hippocampal cells: impact on neuronal morphology and synaptic density.
abstract: Endocrine fibroblast growth factor 23 (FGF23) is predominantly secreted by osteocytes and facilitates renal phosphate excretion. However, FGF23 is also present in cerebrospinal fluid. In chronic kidney disease, FGF23 serum levels are excessively elevated and associated with learning and memory deficits. Structural plasticity of the hippocampus such as formation of new synapses or an altered dendritic arborization comprises a cellular and morphological correlate of memory formation. Therefore, we hypothesize that FGF23 alters hippocampal neuron morphology and synapses. To address this, we prepared primary murine hippocampal cultures and incubated them with recombinant FGF23 alone or together with a soluble isoform of its co-receptor α-Klotho. Neuronal expression of a fluorescent reporter allowed for a detailed evaluation of the neuronal morphology by Sholl analysis. Additionally, we evaluated synaptic density, identified by stainings, for synaptic markers. We show an enhanced number of primary neurites combined with a reduced arborization, resulting in a less complex morphology of neurons treated with FGF23. Moreover, FGF23 enhances the synaptic density in a FGF-receptor (FGF-R) dependent manner. Finally, we addressed the corresponding signaling events downstream of FGF-R employing a combination of western blots and quantitative immunofluorescence. Interestingly, FGF23 induces phospholipase Cγ activity in primary hippocampal neurons. Co-application of soluble α-Klotho leads to activation of the Akt-pathway and modifies FGF23-impact on neuronal morphology and synaptic density. Compared with other FGFs, this alternative signaling pattern is a possible reason for differential effects of FGF23 on hippocampal neurons and may thereby contribute to learning and memory deficits in chronic kidney disease patients. In this study, we show that fibroblast growth factor 23 inhibits neuronal ramification and enhances the synaptic density in primary hippocampal cultures accompanied by phospholipase Cγ-activation. Co-application of the co-receptor α-Klotho leads to an Akt-activation and further modifies neuronal morphology and number of synapses. Those effects provide a mechanistic basis for memory deficits in patients suffering from chronic kidney disease (CKD) characterized by excessively elevated FGF23 levels as well as memory deficits.
authors.affiliation: Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Niko
authors.initials: N
authors.lastname: Hensel
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schön
authors.affiliation: Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Konen
authors.affiliation: Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany.|Center of Systems Neuroscience (ZSN) Hannover, Hannover, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Lübben
authors.affiliation: Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Förthmann
authors.affiliation: Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Baron
authors.affiliation: Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany.|Center of Systems Neuroscience (ZSN) Hannover, Hannover, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Grothe
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Leifheit-Nestler
authors.affiliation: Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany.|Center of Systems Neuroscience (ZSN) Hannover, Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Claus
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Haffner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
chemical_list: C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: Hippocampus; Sholl analysis; chronic kidney disease; cognitive impairment; neurotrophic; phospholipase Cγ