title: Timp-3 deficiency impairs cognitive function in mice.
abstract: Extracellular matrix (ECM) degradation is performed primarily by matrix metalloproteinases (MMPs). MMPs have recently been shown to regulate synaptic activity in the hippocampus and to affect memory and learning. The tissue inhibitor of metalloproteinase (Timp) is an endogenous factor that controls MMP activity by binding to the catalytic site of MMPs. At present, four Timp isotypes have been reported (Timp-1 through Timp-4) with 35-50% amino-acid sequence homology. Timp-3 is a unique member of Timp proteins in that it is bound to the ECM. In this study, we used the passive avoidance test, active avoidance test, and water maze test to examine the cognitive function in Timp-3 knockout (KO) mice. Habituation was evaluated using the open-field test. The water maze test showed that Timp-3 KO mice exhibit deterioration in cognitive function compared with wild-type (WT) mice. The open-field test showed decreased habituation of Timp-3 KO mice. Immunostaining of brain slices revealed the expression of Timp-3 in the hippocampus. In situ zymography of the hippocampus showed increased gelatinolytic activity in Timp-3 KO mice compared with WT mice. These results present the first evidence of Timp-3 involvement in cognitive function and hippocampal MMP activity in mice. Moreover, our findings suggest a novel therapeutic target to be explored for improvement of cognitive function in humans.
authors.affiliation: Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Baba
authors.forename: Osamu
authors.initials: O
authors.lastname: Yasuda
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Takemura
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohishi
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Doe
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Keisuke
authors.initials: K
authors.lastname: Fukuo
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D018093:Gelatinases / Q000378:metabolism; D006185:Habituation, Psychophysiologic; D006624:Hippocampus / Q000201:enzymology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D018093:Gelatinases