Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice.
In the present study we trained tissue-plasminogen activator (tPA)-knockout (tPA -/-) and wild-type (tPA +/+) male mice in step-down inhibitory avoidance learning, a hippocampus-dependent task. tPA -/- displayed significantly shorter latencies to step down at 90 min, one, two and seven days after training indicating the learning deficit in these animals (P < 0.05 vs tPA +/+). The locomotor activity, the level of anxiety in an elevated-plus maze, as well as the pain threshold did not differ between the two strains of mice. The learning disability of tPA -/- was overcome by more intense training. The learning deficit was also partially restored by limited intrahippocampal delivery of tPA (infused for 2 h before training; P < 0.05 vs control), but not by the delivery of urokinase plasminogen activator, indicating the acute need for tPA in learning. The beneficial effect of tPA was abolished by co-infusion of its inhibitor tPA-STOP, indicating that the facilitatory effect of tPA on learning requires a proteolytic step. However, tPA activity in the hippocampus was not indispensable for effective memory retrieval in tPA-infused tPA -/- mice. Thus, rapid, specific and proteolytic action of tPA facilitates hippocampus-dependent learning, but not retrieval of previously acquired information.
Department of Physiology, Hamamatsu University School of Medicine, 3600, Handa-cho, Hamamatsu 431-3192, Japan.
R
R
Pawlak
N
N
Nagai
T
T
Urano
D
D
Napiorkowska-Pawlak
H
H
Ihara
Y
Y
Takada
D
D
Collen
A
A
Takada
D000818:Animals; D001007:Anxiety / Q000201:enzymology / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002384:Catalysis; D006624:Hippocampus / Q000201:enzymology*; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017288:Pain Threshold / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D010959:Tissue Plasminogen Activator