{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:33:50Z","timestamp":1790393630880,"version":"4.1.0"},"reference-count":75,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,3,7]],"date-time":"2016-03-07T00:00:00Z","timestamp":1457308800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004350","name":"Studienstiftung des Deutschen Volkes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004350","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>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\u2010receptor \u03b1\u2010Klotho. 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\u2010receptor (FGF\u2010R) dependent manner. Finally, we addressed the corresponding signaling events downstream of FGF\u2010R employing a combination of western blots and quantitative immunofluorescence. Interestingly, FGF23 induces phospholipase C\u03b3 activity in primary hippocampal neurons. Co\u2010application of soluble \u03b1\u2010Klotho leads to activation of the Akt\u2010pathway and modifies FGF23\u2010impact 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.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13585-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>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 C\u03b3\u2010activation. Co\u2010application of the co\u2010receptor \u03b1\u2010Klotho leads to an Akt\u2010activation 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.\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13585","type":"journal-article","created":{"date-parts":[[2016,2,20]],"date-time":"2016-02-20T21:47:19Z","timestamp":1456004839000},"page":"756-769","source":"Crossref","is-referenced-by-count":72,"title":["Fibroblast growth factor 23 signaling in hippocampal cells: impact on neuronal morphology and synaptic density"],"prefix":"10.1111","volume":"137","author":[{"given":"Niko","family":"Hensel","sequence":"first","affiliation":[{"name":"Institute of Neuroanatomy Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Sch\u00f6n","sequence":"additional","affiliation":[{"name":"Department of Pediatric Kidney Liver and Metabolic Diseases Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Konen","sequence":"additional","affiliation":[{"name":"Institute of Neuroanatomy Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"L\u00fcbben","sequence":"additional","affiliation":[{"name":"Institute of Neuroanatomy Hannover Medical School Hannover Germany"},{"name":"Center of Systems Neuroscience (ZSN) Hannover Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"F\u00f6rthmann","sequence":"additional","affiliation":[{"name":"Institute of Neuroanatomy Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Baron","sequence":"additional","affiliation":[{"name":"Institute of Neuroanatomy Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Grothe","sequence":"additional","affiliation":[{"name":"Institute of Neuroanatomy Hannover Medical School Hannover Germany"},{"name":"Center of Systems Neuroscience (ZSN) Hannover Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Leifheit\u2010Nestler","sequence":"additional","affiliation":[{"name":"Department of Pediatric Kidney Liver and Metabolic Diseases Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Claus","sequence":"additional","affiliation":[{"name":"Institute of Neuroanatomy Hannover Medical School Hannover Germany"},{"name":"Center of Systems Neuroscience (ZSN) Hannover Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Haffner","sequence":"additional","affiliation":[{"name":"Department of Pediatric Kidney Liver and Metabolic Diseases Hannover Medical School Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,3,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(94)91188-6"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-0233"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.17.7834"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1973.sp010273"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709805104"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4477-10.2011"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.115568"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/neu.20100"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.437"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46122"},{"key":"e_1_2_8_12_1","first-page":"199","article-title":"Correlations between performance on neuropsychological tests in children with chronic renal failure","volume":"10","author":"Fennell R. S.","year":"1990","journal-title":"Child Nephrol. Urol."},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.099655"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010-0142"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2010.04.026"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/09297040600876311"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2006.12.001"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.844506"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1551-10.2010"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/tri.12510"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031202"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1037\/a0016221"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00604.x"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.47"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0168-0102(91)90071-6"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4781(02)00281-6"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-010-1024-2"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gft065"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00774-016-0746-y"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/36285"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C500457200"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1301"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2003.00328.x"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-11-5"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2002.02193.x"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2009.02.009"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304544200"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00008.2006"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2011.07.028"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29463"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.8019"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.20022"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02779.x"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2303"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(91)90434-D"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/55.1.278s"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-1878(200002)22:2<108::AID-BIES2>3.0.CO;2-M"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.05840513"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1677\/erc.0.0070165"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023564"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.3727\/096368911X586774"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31827f0f7f"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0361-9230(94)90075-2"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728220902942330"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(82)90120-8"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.0301264"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.12.102"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)00127-6"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/171387a0"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.440677"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-006-0374-1"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2012.03.013"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4402-14.2015"},{"key":"e_1_2_8_65_1","doi-asserted-by":"crossref","first-page":"3932","DOI":"10.1523\/JNEUROSCI.21-11-03932.2001","article-title":"Fibroblast growth factor\u20102 promotes axon branching of cortical neurons by influencing morphology and behavior of the primary growth cone","volume":"21","author":"Szebenyi G.","year":"2001","journal-title":"J. Neurosci."},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002163"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05315"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2005.05.005"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22680"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6332"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.3696"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2014.00006"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0670"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1177\/1073858410371513"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M601252200"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2006.10.019"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.13585","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.13585","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.13585","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T12:16:35Z","timestamp":1696248995000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.13585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,7]]},"references-count":75,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016,6]]}},"alternative-id":["10.1111\/jnc.13585"],"URL":"https:\/\/doi.org\/10.1111\/jnc.13585","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,7]]}}}