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Published on: June 22, 2015
Timp-3 deficiency impairs cognitive function in mice
Yoshichika Baba1, Osamu Yasuda, Yukihiro Takemura
1Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
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.
Insights
Tissue inhibitor of metalloproteinase-3 (Timp-3) deficiency impairs cognitive function and habituation in mice. This study reveals Timp-3
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Extracellular matrix (ECM) degradation is primarily mediated by matrix metalloproteinases (MMPs).
- MMPs play a crucial role in regulating synaptic activity, memory, and learning.
- Tissue inhibitor of metalloproteinases (Timp) proteins, including Timp-3, regulate MMP activity.
Purpose of the Study:
- To investigate the role of Timp-3 in cognitive function and hippocampal MMP activity.
- To assess the impact of Timp-3 deficiency on learning, memory, and habituation.
Main Methods:
- Utilized passive avoidance, active avoidance, and water maze tests to evaluate cognitive function in Timp-3 knockout (KO) mice.
- Assessed habituation using the open-field test.
- Examined hippocampal MMP activity using in situ zymography and Timp-3 expression via immunostaining.
Main Results:
- Timp-3 KO mice demonstrated significant deterioration in cognitive function compared to wild-type (WT) mice in the water maze test.
- Decreased habituation was observed in Timp-3 KO mice during the open-field test.
- Increased gelatinolytic activity was detected in the hippocampus of Timp-3 KO mice, indicating elevated MMP activity.
Conclusions:
- This study provides the first evidence linking Timp-3 to cognitive function and hippocampal MMP regulation in mice.
- Findings suggest that Timp-3 plays a critical role in maintaining cognitive processes.
- Timp-3 emerges as a potential therapeutic target for improving cognitive deficits in humans.
