title: Urokinase-type plasminogen activator receptor modulates epileptogenesis in mouse model of temporal lobe epilepsy.
abstract: Mutation in Plaur gene encoding urokinase-type plasminogen activator receptor (uPAR) results in epilepsy and autistic phenotype in mice. In humans, a single nucleotide polymorphism in PLAUR gene represents a risk for autism spectrum disorders. Importantly, the expression of uPAR is elevated in the brain after various epileptogenic insults like traumatic brain injury and status epilepticus. So far, the consequences of altered uPAR expression on brain networks are poorly known. We tested a hypothesis that uPAR regulates post-injury neuronal reorganization and consequent functional outcome, particularly epileptogenesis. Epileptogenesis was induced by intrahippocampal injection of kainate in adult male wild type (Wt) or uPAR knockout (uPAR-/-) mice, and animals were monitored with continuous (24/7) video-electroencephalogram for 30 days. The severity of status epilepticus did not differ between the genotypes. The spontaneous electrographic seizures which developed were, however, longer and their behavioral manifestations were more severe in uPAR-/- than Wt mice. The more severe epilepsy phenotype in uPAR-/- mice was associated with delayed but augmented inflammatory response and more severe neurodegeneration in the hippocampus. Also, the distribution of newly born cells in the dentate gyrus was more scattered, and the recovery of hippocampal blood vessel length from status epilepticus-induced damage was compromised in uPAR-/- mice as compared to Wt mice. Our data demonstrate that a deficiency in uPAR represents a mechanisms which results in the development of a more severe epilepsy phenotype and progressive brain pathology after status epilepticus. We suggest that uPAR represents a rational target for disease-modifying treatments after epileptogenic brain insults.
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P. O. Box 1627, 70 211 Kuopio, Finland. xavier.ekollendode-ekane@uef.fi
authors.forename: Xavier Ekolle
authors.initials: XE
authors.lastname: Ndode-Ekane
authors.forename: Asla
authors.initials: A
authors.lastname: Pitkänen
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D001831:Body Temperature; D002465:Cell Movement; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D005838:Genotype; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007608:Kainic Acid / Q000008:administration & dosage; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019599:Mossy Fibers, Hippocampal / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D055495:Neurogenesis; D009479:Neuropeptides / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C524899:Plaur protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; D007608:Kainic Acid