Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin.
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.
Madani
Rime
R
Institute of Anatomy, University of Zurich, Zurich CH-8057, Switzerland.
Kozlov
Serguei
S
Akhmedov
Alexander
A
Cinelli
Paolo
P
Kinter
Jochen
J
Lipp
Hans-Peter
HP
Sonderegger
Peter
P
Wolfer
David Paul
DP
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
D009479:Neuropeptides; D012697:Serine Endopeptidases; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin