The brain-tumor related protein podoplanin regulates synaptic plasticity and hippocampus-dependent learning and memory

Abstract

Introduction: 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. Materials and methods: Using an established podoplanin-knockout mouse model and electrophysiological, biochemical, and behavioral approaches, we investigated the brain neuronal role of podoplanin. Results: 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. Discussion: 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 messagesPodoplanin, 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.

Cell motility and migration as determinants of stem cell efficacy

“…4g ) in the 3xTg-AD mice. PDPN is also a regulator of synaptic plasticity and hippocampus-dependent learning and memory in mice [38] . Therefore, PDPN release by transplanted (PDPN overexpressing) SC may both increase their migration and alleviate synaptic dysfunction and memory deficits in AD.…”

Nicotine abolishes memory‐related synaptic strengthening and promotes synaptic depression in the neurogenic dentate gyrus of miR‐132/212 knockout mice

“…Brain extraction and whole hippocampi isolation from miRNA‐132/212 −/− and WT male mice ( n = 6 animals per group) were conducted according to methods established in our laboratory as described before, 66–68 with minor modifications 69 . Animals were euthanized by quick cervical dislocation, followed by a swift sharp‐blade decapitation.…”

“…Acute hippocampal slices were prepared from miRNA‐132/212 −/− and littermate WT male mice ( n = 5–6 animals per group) according to a previously published protocols, 66–68,70 with minor modifications. Following quick cervical dislocation and swift sharp‐blade decapitation, brains were extracted by a midline incision in the occipital bone starting at the foramen magnum extending to the sutura frontalis.…”

“…Electrical stimulation was delivered via customized Teflon‐coated tungsten wire bipolar stimulating electrodes isolated to the tip (~50‐μm diameter tip). Recordings of fEPSPs were obtained from the dentate gyri middle molecular cell layer upon stimulation of the medial perforant pathway (MPP) as previously described by our group and others 68,71 . Standard input/output (I/O) curves were generated by plotting the data obtained for different series of fEPSP field slopes (by using linear fit on each trace starting from 20% and ending at 80% of the decaying phase) as measured in response to increasing square pulses (200 μs, 15‐s interpulse interval, 0–9 V and 1‐V increments) of electrical stimulation.…”

Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria

“…Long-term potentiation (LTP) and basal synaptic transmission (Input/Output (I/O) curve and paired-pulse inhibition (PPI)) were evaluated in acutely dissected hippocampal slices. The procedures for the hippocampal slice preparation and electrophysiological recordings followed previously published protocols with some minor modifications [32]. Briefly, mice were killed and hippocampi were dissected under the microscope.…”