title: The brain-tumor related protein podoplanin regulates synaptic plasticity and hippocampus-dependent learning and memory.
abstract: Podoplanin 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.
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Ana
authors: A
authors: Cicvaric
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Jiaye
authors: J
authors: Yang
authors: b Clinical Institute of Pathology , Medical University of Vienna , Vienna , Austria.
authors: Sigurd
authors: S
authors: Krieger
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Deeba
authors: D
authors: Khan
authors: c Paik Institute for Clinical Research, Inje University College of Medicine , Busan , Republic of Korea.
authors: Eun-Jung
authors: EJ
authors: Kim
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Manuel
authors: M
authors: Dominguez-Rodriguez
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Maureen
authors: M
authors: Cabatic
authors: d Psychology University of York , Heslington York , UK.
authors: Barbara
authors: B
authors: Molz
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Juan Pablo
authors: JP
authors: Acevedo Aguilar
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Radoslav
authors: R
authors: Milicevic
authors: e Grupo de Fisiopatología Cardiovascular, Instituto de Biomedicina de Sevilla (IBiS) , Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla , Seville , Spain.
authors: Tarik
authors: T
authors: Smani
authors: f Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Johannes M
authors: JM
authors: Breuss
authors: b Clinical Institute of Pathology , Medical University of Vienna , Vienna , Austria.
authors: Dontscho
authors: D
authors: Kerjaschki
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Daniela D
authors: DD
authors: Pollak
authors: f Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Pavel
authors: P
authors: Uhrin
authors: a Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology , Medical University of Vienna , Vienna , Austria.
authors: Francisco J
authors: FJ
authors: Monje
mesh_terms: D000818:Animals; D055786:Gene Knockout Techniques; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D009473:Neuronal Plasticity; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; C490441:Pdpn protein, mouse; D000098853:Podoplanin
keywords: Ezrin; Podoplanin; dentate gyrus; hippocampus; memory; nerve growth factor; neuron; synaptic plasticity