title: Vascular endothelial growth factor up-regulation in the mouse hippocampus and its role in the control of epileptiform activity.
abstract: The vascular endothelial growth factor (VEGF) signalling pathway may represent an endogenous anti-convulsant in the rodent hippocampus although its exact contribution requires some clarification. In mouse hippocampal slices, the potassium channel blocker 4-aminopyridine (4-AP) in the absence of external Mg(2+)(0 Mg(2+)) produces both ictal and interictal activity followed by a prolonged period of repetitive interictal activity. In this model, we demonstrated that exogenous VEGF has clear effects on ictal and interictal activity as it reduces the duration of ictal-like events, but decreases the frequency and intensity of interictal discharges. VEGF affects epileptiform activity through its receptor VEGFR-2. We also demonstrated for the first time that the synaptic action of VEGF in the hippocampus is through VEGFR-2-mediated effects on NMDA and GABA(B) receptors and that VEGF does not affect the NMDA excytatory postsynaptic potential paired-pulse facilitation ratio. Exogenous VEGF does not affect the AMPA-mediated responses and the dendritic or the somatic GABA(A) inhibitory postsynaptic potentials. In addition, VEGF drastically reduces 0 Mg(2+)/4-AP-induced glutamate release through VEGFR-2 activation. In vitro epileptiform activity is sufficient to increase hippocampal expression of VEGF and VEGFR-2, and this up-regulation may serve a neuroprotective and/or anti-convulsant role. VEGFR-2 up-regulation has been localized to the CA1 region, which suggests that VEGF signalling may protect CA1 pyramidal cells from hyperexcitability. These results indicate that VEGF controls epileptic activity by influencing both glutamatergic and GABAergic transmission and further advance our understanding of the conditions required for endogenous VEGF up-regulation, and the mechanisms by which VEGF achieves an anti-convulsant effect.
authors.affiliation: Unit of General Physiology, Department of Biology, University of Pisa, via San Zeno 31, 56127 Pisa, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cammalleri
authors.forename: Davide
authors.initials: D
authors.lastname: Martini
authors.forename: Chiara
authors.initials: C
authors.lastname: Ristori
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Timperio
authors.forename: Paola
authors.initials: P
authors.lastname: Bagnoli
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D018080:Receptors, GABA-B / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2