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First published online 19 August 2008
doi: 10.1242/jcs.035063

Journal of Cell Science 121, 3042-3051 (2008)
Published by The Company of Biologists 2008
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Synapsin-I- and synapsin-II-null mice display an increased age-dependent cognitive impairment

Anna Corradi1, Alessio Zanardi2, Caterina Giacomini1, Franco Onofri1, Flavia Valtorta3, Michele Zoli2 and Fabio Benfenati1,4,*

1 Department of Experimental Medicine, Section of Physiology, University of Genova and Istituto Nazionale di Neuroscienze, Viale Benedetto XV, 3 16132 Genova, Italy
2 Department of Biomedical Sciences, Section of Physiology, University of Modena, Via Campi 287, 41100 Modena, Italy
3 San Raffaele Scientific Institute/Vita-Salute University, IIT Unit of Molecular Neuroscience and Istituto Nazionale di Neuroscienze, via Olgettina 58, 20132 Milano, Italy
4 Department of Neuroscience and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy


Figure 1
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  		Fig. 1. SynII–/– mice display impaired spatial learning during aging. The Morris-water-maze performance of WT, SynI–/– and SynII–/– mice was analyzed in young (A,B), adult (C,D) and aged (E,F) mice (eight or nine mice per group). (A,C,E) Learning curves for training to find the hidden platform in the Morris water maze are shown. The latencies to find the platform in the four daily sessions, performed over a period of up to 8 days, were averaged to obtain one value/animal/day and the data are shown as means ± s.e.m. Statistical analysis of the overall learning curves was performed by using one-way ANOVA for repeated measures. Young: F(4,31)Time = 35.28, P<0.001; F(2,31)Groups = 2.41, not significant. Adult: F(6,34)Time = 41.36, P<0.001; F(2,34)Groups = 5.79, P<0.01. Aged: F(7,27)Time = 19.71, P<0.001; F(2,27)Groups = 5.30, P~0.01. This was followed by Bonferroni's multiple comparison test (*P<0.05 and **P<0.01 for either mutant strain vs WT; °P<0.05 for SynI–/– vs SynII–/–). (B,D,F) Illustrate the results of the transfer test, performed on the day immediately after the last training session, in which the platform was removed and the animals were allowed to swim for 1 minute. The percentage of time spent by each mouse in the correct quadrant (the quadrant holding the hidden platform during the previous training sessions) and the overall distance covered during the test are shown on the left and right y-axes, respectively, as means ± s.e.m. Statistical analysis of the transfer test was performed by using one-way ANOVA [young: F(2,33) = 0.58, not significant; adult: F(2,36) = 6.71, P<0.005; aged: F(2,29) = 4.32, P<0.05] followed by the Bonferroni's post-hoc test (*P<0.05 for either mutant strain vs WT; °P<0.05 and °°P<0.01 for SynI–/– vs SynII–/–).

 

Figure 2
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  		Fig. 2. Memory for objects is impaired during aging in both SynI–/– and SynII–/– mice. The object-recognition performance of WT, SynI–/– and SynII–/– mice was analyzed in young (A), adult (B) and aged (C) mice (eight to ten mice per group). The two test sessions were carried out 3 and 24 hours after the presentation of the first pairs of objects and the percentage of time spent on the new object was plotted as means ± s.e.m. Statistical analysis was performed by using one-way ANOVA. Young: F(2,27)Time 0hrs = 0.91, not significant; F(2,27)Time 3hrs = 0.41, not significant; F(2,27)Time 24hrs = 0.94, not significant. Adult: F(2,35)Time 0hrs = 1.15, not significant; F(2,35)Time 3hrs = 1.88, not significant; F(2,35)Time 24hrs = 5.38, P<0.01. Aged: F(2,30)Time 0hrs = 2.79, not significant; F(2,30)Time 3hrs = 0.94, not significant; F(2,30)Time 24hrs =16.93, P<0.001. This was followed by the Bonferroni's multiple comparison test (*P<0.05, **P<0.01 and ***P<0.001 for either SynI–/– or SynII–/– vs WT).

 

Figure 3
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  		Fig. 3. Emotional memory is impaired during aging in both SynI–/– and SynII–/– mice. Conditioned fear displayed by WT, SynI–/– and SynII–/– mice was evaluated in young (A), adult (B) and aged (C) mice (eight to ten mice per group). The test session was carried out 24 hours after conditioning and the percentage of time spent freezing is shown as means ± s.e.m. Statistical analysis was carried out by using the one-way ANOVA followed by the Bonferroni's multiple comparison test. Contextual test: F(2,27)Young = 1.33, not significant; F(2,33)Adult = 15.53, P<0.001; F(2,26)Aged = 12.29, P<0.001. Cued test: F(2,27)Young = 0.24, not significant; F(2,33)Adult = 6.44, P<0.005; F(2,26)Aged = 44.22, P<0.001. Bonferroni's multiple comparison test vs WT: *P<0.05; **P<0.01; ***P<0.001.

 

Figure 4
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  		Fig. 4. Aged SynI–/– and SynII–/– mice have an increased neuronal loss in the CA1 region of the hippocampus. (A) Schematic drawing of a coronal section of mouse brain at bregma level –1.55 mm (modifed from the Allen Reference Atlas, http://www.brain-map.org/welcome.do). The boxed area corresponds to the region of the hippocampal field CA1 that was sampled in young (C) and aged (B,C) WT, SynI–/– and SynII–/– mice (11-12 mice per group). (B) Immunostaining with anti-NeuN antibody of 10-µm cryostat sections of the CA1 region of aged WT, SynI–/– and SynII–/– brains. Scale bar: 10 µm. (C) The counts of NeuN-stained nuclei in the sampled area of young and aged mice, plotted as mean percent changes ± s.e.m. with respect to age-matched WT mice, show a loss of pyramidal neurons in the CA1 hippocampal field of aged mutant mice. The counts of NeuN-stained nuclei/sampled area in WT mice were 97.0±2.9 and 102.9±2.0 for young and aged mice, respectively. Statistical analysis was performed by means of one-way ANOVA [F(2,32)=10.97, P<0.001] followed by Bonferroni's multiple comparison test (*P<0.05, ***P<0.001 vs WT).

 

Figure 5
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  		Fig. 5. Aged SynI–/– and SynII–/– mice have an increased neuronal loss in the neocortex. (A) Immunostaining with anti-NeuN antibody of 10-µm cryostat sections of the somatosensory cortex of aged WT, SynI–/– and SynII–/– brains (eight mice per group). Scale bar: 50 µm. (B) Schematic drawing of a coronal section of mouse brain at bregma level –1.55 mm (modified from the Allen Reference Atlas, http://www.brain-map.org/welcome.do), showing the sampled region of the somatosensory cortex that was analyzed (boxed area). (C) The number of NeuN-stained nuclei counted in the sampled area of young and aged mice, plotted as mean percent changes ± s.e.m. with respect to age-matched WT mice, showed a significant neuronal loss in aged mutant mice. The counts of NeuN-stained nuclei/sampled area in WT mice were 946.7±36.5 and 907.6±37.5 for young and aged mice, respectively. Statistical analysis was performed by means of one-way ANOVA [F(2,20) = 12.94, P<0.001] followed by Bonferroni's multiple comparison test (**P<0.01, ***P<0.001 vs WT).

 

Figure 6
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  		Fig. 6. Aged SynII–/– but not SynI–/–, mice display increased astrogliosis in the CA1 region of the hippocampus. (A) Immunostaining with anti-GFAP antibodies of 10-µm cryostat sections of the CA1 hippocampal field of aged WT, SynI–/– and SynII–/– brains (9-12 mice per group). Scale bar: 50 µm. (B) Schematic drawing of a coronal section of mouse brain at bregma level –1.55 mm (modifed from the Allen Reference Atlas, http://www.brain-map.org/welcome.do), showing the sampled region of the hippocampal field CA1 (boxed area). (C) The GFAP immunopositive field area was measured and is expressed as a percentage of the total sampled area. The data, plotted as means ± s.e.m., showed a selective increase in the GFAP-immunoreactive area (+24.5±5%) in SynII–/– mice with respect to age-matched WT or SynI–/– mice. Statistical analysis was performed by means of one-way ANOVA [F(2,31) = 9.65, P<0.001] followed by Bonferroni's multiple comparison test (***P<0.001 SynII–/– vs WT mice; °P<0.05 SynII–/– vs SynI–/– mice).

 

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© The Company of Biologists Ltd 2008