title: Urokinase-type plasminogen activator deficiency has little effect on seizure susceptibility and acquired epilepsy phenotype but reduces spontaneous exploration in mice.
abstract: Urokinase-type plasminogen activator (uPA), a serine protease, converts plasminogen to plasmin. Activation of plasmin leads to degradation of the extracellular matrix, which is critical for tissue recovery, angiogenesis, cell migration, and axonal and synaptic plasticity. We hypothesized that uPA deficiency would cause an abnormal neurophenotype and would lead to exacerbated epileptogenesis after brain injury. Wild-type (Wt) and uPA-/- mice underwent a battery of neurologic behavioral tests evaluating general reactivity, spontaneous exploratory activity, motor coordination, pain threshold, fear and anxiety, and memory. We placed particular emphasis on the effect of uPA deficiency on seizure susceptibility, including the response to convulsants (pentylenetetrazol, kainate, or pilocarpine) and kainate-induced epileptogenesis and epilepsy. The uPA-/- mice showed no motor or sensory impairment compared with the Wt mice. Hippocampus-dependent spatial memory also remained intact. The uPA-/- mice, however, exhibited reduced exploratory activity and an enhanced response to a tone stimulus (p<0.05 compared with the Wt mice). The urokinase-type plasminogen activator deficient mice showed no increase in spontaneous or evoked epileptiform electrographic activity. Rather, the response to pilocarpine administration was reduced compared with the Wt mice (p<0.05). Also, the epileptogenesis and the epilepsy phenotype after intrahippocampal kainate injection were similar to those in the Wt mice. Taken together, uPA deficiency led to diminished interest in the environmental surroundings and enhanced emotional reactivity to unexpected aversive stimuli. Urokinase-type plasminogen activator deficiency was not associated with enhanced seizure susceptibility or worsened poststatus epilepticus epilepsy phenotype.
authors.affiliation: Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Rantala
authors.affiliation: Neurobiology of Memory Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Kemppainen
authors.affiliation: Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: X E
authors.initials: XE
authors.lastname: Ndode-Ekane
authors.affiliation: Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Lahtinen
authors.affiliation: Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Tamuna
authors.initials: T
authors.lastname: Bolkvadze
authors.affiliation: Neurobiology of Memory Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Gurevicius
authors.affiliation: Neurobiology of Memory Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Tanila
authors.affiliation: Epilepsy Research Laboratory, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, PO Box 1777, FIN-70211 Kuopio, Finland. Electronic address: asla.pitkanen@uef.fi.
authors.forename: A
authors.initials: A
authors.lastname: Pitkänen
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D004198:Disease Susceptibility; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012640:Seizures / Q000503:physiopathology*; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator
keywords: Anxiety; Epileptogenesis; Memory; Neurophenotyping; Social anxiety; uPAR interactome