Impaired memory retention and decreased long-term potentiation in integrin-associated protein-deficient mice

Abstract

Previously, we have demonstrated that integrin-associated protein (IAP) mRNA level is approximately fourfold higher in rats showing good retention performance (600 sec) than rats showing poor retention performance (< 80 sec) in an inhibitory avoidance learning paradigm. In the present study, we have used the gene-targeted IAP-deficient mice to further investigate the role of IAP involved in memory formation and hippocampal long-term potentiation (LTP) in vivo. Results revealed that there was a significant impairment in memory retention and a significant reduction in the magnitude of LTP in IAP-deficient mice when compared with the wild-type and heterozygote mice, whereas the wild-type and heterozygote animals did not show marked differences on these measures. Furthermore, the impairment in retention performance of IAP-deficient mice was not due to different sensitivities of these animals to the electric shock. When we examined locomotor activity and rotarod treadmill performance, no differences were observed among these three groups of animals either. Western blot analysis confirmed the lack of IAP protein in IAP-deficient mice, whereas IAP expression was similar in both the wild-type and heterozygote controls. These results together demonstrate that IAP plays an important role in the process of memory formation and synaptic plasticity in mice.

Figure 1

(A) Retention performance of homozygote (IAP^+/+, n = 13), heterozygote (IAP^+/−, n = 11), and IAP knockout (IAP^−/−, n = 17) mice in an inhibitory avoidance learning task. Data are expressed as median ± interquartile range. The comparisons between IAP^+/+ and IAP^−/− groups, as well as between the IAP^+/− and IAP^−/− groups, were significant (both P < 0.05, Mann-Whitney one-tailed U test. (B) Locomotor activity level of the same mice measured in a digiscan activity monitor for 20 min (P > 0.05). (C) Endurance time of the same animals measured in a rotarod treadmill (P > 0.05). Data are expressed as mean ±s.e.m. in B and C.

Figure 1

(A) Retention performance of homozygote (IAP^+/+, n = 13), heterozygote (IAP^+/−, n = 11), and IAP knockout (IAP^−/−, n = 17) mice in an inhibitory avoidance learning task. Data are expressed as median ± interquartile range. The comparisons between IAP^+/+ and IAP^−/− groups, as well as between the IAP^+/− and IAP^−/− groups, were significant (both P < 0.05, Mann-Whitney one-tailed U test. (B) Locomotor activity level of the same mice measured in a digiscan activity monitor for 20 min (P > 0.05). (C) Endurance time of the same animals measured in a rotarod treadmill (P > 0.05). Data are expressed as mean ±s.e.m. in B and C.

Figure 1

(A) Retention performance of homozygote (IAP^+/+, n = 13), heterozygote (IAP^+/−, n = 11), and IAP knockout (IAP^−/−, n = 17) mice in an inhibitory avoidance learning task. Data are expressed as median ± interquartile range. The comparisons between IAP^+/+ and IAP^−/− groups, as well as between the IAP^+/− and IAP^−/− groups, were significant (both P < 0.05, Mann-Whitney one-tailed U test. (B) Locomotor activity level of the same mice measured in a digiscan activity monitor for 20 min (P > 0.05). (C) Endurance time of the same animals measured in a rotarod treadmill (P > 0.05). Data are expressed as mean ±s.e.m. in B and C.

Figure 2

Representative illustrations showing a single response in population spike of (A) IAP^+/+, (B) IAP^+/−, and (C) IAP^−/− mice. (D) Tetanic stimulation-induced LTP in IAP^+/+ (n = 5), IAP^+/− (n = 5), and IAP^−/− (n = 6) mice. A significant reduction in the slope of pEPSP in IAP^−/− mice (○) was observed when compared to the IAP^+/+ (█) and IAP^+/− (●) groups (both P < 0.05, one-way ANOVA followed by Dunnett's t-test). There was no marked difference between IAP^+/+ and IAP^+/− groups (P > 0.05). (E) As in D, a significant reduction in the amplitude of population spike was also observed in IAP^−/− mice when compared with IAP^+/+ and IAP^+/− mice (both P < 0.05). Again, no marked difference was observed between IAP^+/+ and IAP^+/− groups (P > 0.05) (symbols the same as in D). Data are expressed as mean ±s.e.m.. Arrow indicates tetanic stimulation.

Figure 2

Representative illustrations showing a single response in population spike of (A) IAP^+/+, (B) IAP^+/−, and (C) IAP^−/− mice. (D) Tetanic stimulation-induced LTP in IAP^+/+ (n = 5), IAP^+/− (n = 5), and IAP^−/− (n = 6) mice. A significant reduction in the slope of pEPSP in IAP^−/− mice (○) was observed when compared to the IAP^+/+ (█) and IAP^+/− (●) groups (both P < 0.05, one-way ANOVA followed by Dunnett's t-test). There was no marked difference between IAP^+/+ and IAP^+/− groups (P > 0.05). (E) As in D, a significant reduction in the amplitude of population spike was also observed in IAP^−/− mice when compared with IAP^+/+ and IAP^+/− mice (both P < 0.05). Again, no marked difference was observed between IAP^+/+ and IAP^+/− groups (P > 0.05) (symbols the same as in D). Data are expressed as mean ±s.e.m.. Arrow indicates tetanic stimulation.

Figure 2

Representative illustrations showing a single response in population spike of (A) IAP^+/+, (B) IAP^+/−, and (C) IAP^−/− mice. (D) Tetanic stimulation-induced LTP in IAP^+/+ (n = 5), IAP^+/− (n = 5), and IAP^−/− (n = 6) mice. A significant reduction in the slope of pEPSP in IAP^−/− mice (○) was observed when compared to the IAP^+/+ (█) and IAP^+/− (●) groups (both P < 0.05, one-way ANOVA followed by Dunnett's t-test). There was no marked difference between IAP^+/+ and IAP^+/− groups (P > 0.05). (E) As in D, a significant reduction in the amplitude of population spike was also observed in IAP^−/− mice when compared with IAP^+/+ and IAP^+/− mice (both P < 0.05). Again, no marked difference was observed between IAP^+/+ and IAP^+/− groups (P > 0.05) (symbols the same as in D). Data are expressed as mean ±s.e.m.. Arrow indicates tetanic stimulation.

Figure 3

Representative gel pattern showing the results of Western blotting of IAP expression in the whole brain of IAP^+/+, IAP^+/−, and IAP^−/− mice. IAP monoclonal antibody (miap301; Lindberg et al. 1996b) was used. IAP protein was absent in IAP^−/− mice and IAP expression was similar in both IAP^+/+ and IAP^+/− mice.