Cicvaric, AnaYang, JiayeKrieger, SigurdKhan, DeebaKim, Eun-JungDominguez-Rodriguez, ManuelCabatic, MaureenMolz, BarbaraAcevedo Aguilar, Juan PabloMilicevic, RadoslavSmani, TarikBreuss, Johannes MKerjaschki, DontschoPollak, Daniela DUhrin, PavelMonje, Francisco J2023-01-252023-01-252016-08-25http://hdl.handle.net/10668/10390Podoplanin is a cell-surface glycoprotein constitutively expressed in the brain and implicated in human brain tumorigenesis. The intrinsic function of podoplanin in brain neurons remains however uncharacterized. Using an established podoplanin-knockout mouse model and electrophysiological, biochemical, and behavioral approaches, we investigated the brain neuronal role of podoplanin. Ex-vivo electrophysiology showed that podoplanin deletion impairs dentate gyrus synaptic strengthening. In vivo, podoplanin deletion selectively impaired hippocampus-dependent spatial learning and memory without affecting amygdala-dependent cued fear conditioning. In vitro, neuronal overexpression of podoplanin promoted synaptic activity and neuritic outgrowth whereas podoplanin-deficient neurons exhibited stunted outgrowth and lower levels of p-Ezrin, TrkA, and CREB in response to nerve growth factor (NGF). Surface Plasmon Resonance data further indicated a physical interaction between podoplanin and NGF. This work proposes podoplanin as a novel component of the neuronal machinery underlying neuritogenesis, synaptic plasticity, and hippocampus-dependent memory functions. The existence of a relevant cross-talk between podoplanin and the NGF/TrkA signaling pathway is also for the first time proposed here, thus providing a novel molecular complex as a target for future multidisciplinary studies of the brain function in the physiology and the pathology. Key messages Podoplanin, a protein linked to the promotion of human brain tumors, is required in vivo for proper hippocampus-dependent learning and memory functions. Deletion of podoplanin selectively impairs activity-dependent synaptic strengthening at the neurogenic dentate-gyrus and hampers neuritogenesis and phospho Ezrin, TrkA and CREB protein levels upon NGF stimulation. Surface plasmon resonance data indicates a physical interaction between podoplanin and NGF. On these grounds, a relevant cross-talk between podoplanin and NGF as well as a role for podoplanin in plasticity-related brain neuronal functions is here proposed.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/EzrinPodoplanindentate gyrushippocampusmemorynerve growth factorneuronsynaptic plasticityAnimalsGene Knockout TechniquesHippocampusHumansMembrane GlycoproteinsMemoryMiceNeuronal Plasticityresearch article27558977open access10.1080/07853890.2016.12194551365-2060PMC5125287https://www.tandfonline.com/doi/pdf/10.1080/07853890.2016.1219455?needAccess=truehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125287/pdf