title: Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin.
abstract: Neuroserpin is a neural serpin that inhibits the extracellular protease tissue-type plasminogen activator (tPA). We have generated neuroserpin-deficient mice which are viable and healthy. Zymographic analysis of neuroserpin-deficient brain showed unaltered tPA activity, suggesting that other inhibitors contribute to the regulation of tPA and may compensate for the defect. Analysis of explorative behavior revealed selective reduction of locomotor activity in novel environments, an anxiety-like response on the O-maze, and a neophobic response to novel objects. Mice overexpressing neuroserpin under the control of the Thy1.2 promoter are known to have a reduced brain tPA activity. They showed reduced center exploration in the open-field test and, like neuroserpin-deficient mice, a neophobic phenotype in the novel object test. Our results implicate neuroserpin in the regulation of emotional behavior through a mechanism that is at least in part independent of tPA activity. They are the first evidence for a role of protease inhibitors in mood regulation.
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich CH-8057, Switzerland.
authors.forename: Rime
authors.initials: R
authors.lastname: Madani
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Paolo
authors.initials: P
authors.lastname: Cinelli
authors.forename: Jochen
authors.initials: J
authors.lastname: Kinter
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Lipp
authors.forename: Peter
authors.initials: P
authors.lastname: Sonderegger
authors.forename: David Paul
authors.initials: DP
authors.lastname: Wolfer
mesh_terms: D000339:Affect / Q000502:physiology; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology*; D005110:Extracellular Space / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics*; D010698:Phobic Disorders / Q000503:physiopathology*; D012697:Serine Endopeptidases / Q000378:metabolism; D015843:Serpins / Q000235:genetics*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D000097522:Neuroserpin
chemical_list: D009479:Neuropeptides; D012697:Serine Endopeptidases; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin