Publication: The brain-tumor related protein podoplanin regulates synaptic plasticity and hippocampus-dependent learning and memory.
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Identifiers
Date
2016-08-25
Authors
Cicvaric, Ana
Yang, Jiaye
Krieger, Sigurd
Khan, Deeba
Kim, Eun-Jung
Dominguez-Rodriguez, Manuel
Cabatic, Maureen
Molz, Barbara
Acevedo Aguilar, Juan Pablo
Milicevic, Radoslav
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Volume Title
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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.
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MeSH Terms
Animals
Gene Knockout Techniques
Hippocampus
Humans
Membrane Glycoproteins
Memory
Mice
Neuronal Plasticity
Gene Knockout Techniques
Hippocampus
Humans
Membrane Glycoproteins
Memory
Mice
Neuronal Plasticity
DeCS Terms
CIE Terms
Keywords
Ezrin, Podoplanin, dentate gyrus, hippocampus, memory, nerve growth factor, neuron, synaptic plasticity