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Optimal level activity of matrix metalloproteinases is critical for adult visual plasticity in the healthy and stroke-affected brain

  1. Justyna Pielecka-Fortuna  Is a corresponding author
  2. Evgenia Kalogeraki
  3. Michal G Fortuna
  4. Siegrid Löwel
  1. University of Göttingen, Germany
  2. University Medical Center, Germany
  3. German Primate Center, Germany
Research Article
Cite this article as: eLife 2015;4:e11290 doi: 10.7554/eLife.11290
6 figures and 2 tables

Figures

Treatment with the MMP-inhibitor GM6001 during MD period prevented OD-plasticity in adult mouse V1.

Representative examples of optically recorded activity and polar maps in V1 of both vehicle-treated mice (control, A, C) and animals treated with the MMP-inhibitor GM6001 (GM6001, B, D), before (no MD, A, B) and after monocular deprivation (7 days MD, C, D). V1-maps after visual stimulation of the contra- (contra) and ipsilateral (ipsi) eye in the binocular region of V1. Top panels (A–D) display grayscale-coded response magnitude maps (V1-activation) and their quantification on the right: histogram of (C-I)/(C+I). V1-activation is illustrated as fractional change in reflection ×10-4. Average V1-activation is illustrated as a number at the lower right corner of each magnitude map; the average OD-index (ODI) as a number in the upper right corner of the histograms. Bottom panels represent color-coded polar maps of retinotopy, and the color-coded OD-map. In both control and GM6001-treated mice without MD, V1-activity was dominated by input from the contralateral eye: activity patches after contralateral eye stimulation were darker than after ipsilateral eye stimulation, the average ODI was positive, and warm colors prevailed in the OD-map, illustrating contralateral dominance. After 7 days of MD, OD-plasticity occurred only in control (C) but not in GM6001-treated mice (D): in control mice, both eyes activated V1 rather equally strong, the OD-histogram was shifted to the left (blue arrow in C), and colder colors appeared in the OD-map. In contrast, in GM6001-treated mice, the deprived (contralateral) eye continued to dominate V1, the ODI was not reduced and warm colors still dominated the OD-map. Scale bar: 1mm.

https://doi.org/10.7554/eLife.11290.003
Inhibition of MMPs during the MD-period prevented adult OD-plasticity.

(A) Optically imaged OD-indices in animals without MD (solid symbols) and after 7 days of MD (right half of symbols is black) in control (vehicle-treated, black) and in GM6001-treated mice (grey). Symbols illustrate ODI-values of individual cases; means are marked by horizontal lines. (B) V1-activation elicited by stimulation of the contralateral (C) or ipsilateral (I) eye in animals before (open circles) and after MD (closed eye marked as a black filled circle, and striped bar). The OD-shift in control mice was mediated by an increase of open eye responses in V1, while no OD-shift and no changes in V1-actiavtion were observed in GM6001-treated mice after MD. Mean ± SEM, *p<0.05, **p<0.01, ***p<0.001. ANOVA followed by multiple comparisons with Bonferroni correction was used in A; two-tailed t-test was used in B.

https://doi.org/10.7554/eLife.11290.004
Figure 2—source data 1

Ocular dominance index and V1-activation individual values for Figure 2.

https://doi.org/10.7554/eLife.11290.005
Inhibition of MMPs prevented experience-enabled enhancements of both the spatial frequency (A) and contrast sensitivity (B) thresholds of the optomotor reflex of the open eye in adult mice after MD.

Values of vehicle-treated (control) mice are displayed in black (triangles), values of GM6001-treated mice in grey (circles); values of animals with monocular deprivation (+MD) are marked by displaying the right half of the symbol in black. (A) Spatial frequency threshold values in cycles/degree (cyc/deg), measured in the optomotor setup plotted against days. (B) Contrast sensitivity values on day 7 at 6 different spatial frequencies. Mean ± SEM; ***p<0.001, ns p>0.05. ANOVA followed by multiple comparisons with Bonferroni correction was used; two-tailed t-test was used within the group analysis in A.

https://doi.org/10.7554/eLife.11290.006
Figure 3—source data 1

Optomotry measured spatial frequency and contrast sensitivity thresholds individual values for Figure 3.

https://doi.org/10.7554/eLife.11290.007
A single GM6001-treatment rescued OD-plasticity in V1 after a stroke in S1.

Representative examples of optically recorded activity and polar maps in V1 of both vehicle- (PT+vehicle, A, C) and single GM6001-treated mice (PT+1xGM6001, B, D), before (no MD, A, B) and after 7 days of MD (7days MD, C, D). V1-maps after visual stimulation of the contra- (contra) and ipsilateral (ipsi) eye in the binocular region in V1. Figure layout and data display as in Figure 1. In both vehicle- (A) and GM6001-treated PT-lesioned mice without MD (B), V1 activation was dominated by the contralateral eye: activity patches induced by contralateral eye stimulation were darker than after ipsilateral eye stimulation, the average ODI was positive, and warm colors dominated the OD-map. (C) While 7 days of MD did not induce an OD-shift in vehicle-treated PT mice, and deprived (contra) eye patches still dominated V1, a single treatment with GM6001 rescued OD-plasticity in PT mice (D): both eyes activated V1 about equally strong, the histogram of ODIs shifted to the left (blue arrow) and colder colors appeared in the OD-map. Scale bar: 1mm

https://doi.org/10.7554/eLife.11290.009
Brief MMP-inhibition after a stroke in S1 rescued experience-dependent plasticity in V1.

Quantification of the imaging data, layout and data display as in Figure 2. (A) Optically imaged OD-indices in mice without MD and after 7 days of MD in vehicle-treated 1h after PT (black) mice and single GM6001-treated (PT 1xGM6001; PT+MD 1xGM6001 1 hr and PT+MD 1xGM6001 24 h, light grey) or two-times GM6001-treated (PT+MD 2xGM6001 1 h+24 h, dark grey) after PT mice. (B) V1-activation elicited by stimulation of the contralateral (C) or ipsilateral (I) eye in animals before (open circles) and after MD. V1-activation did not change after MD in vehicle-treated PT mice. In contrast, 1xGM6001 (either 1 h or 24 h) but not 2xGM6001 (1 h+24 h) treatment rescued OD-plasticity after the PT-lesion (A). There was a significant reduction in deprived eye responses in V1 in the GM6001- but not vehicle-treated mice after MD (B). Mean ± SEM, *p<0.05, **p<0.01, ***p<0.001. ANOVA followed by multiple comparisons with Bonferroni correction was used; two-tailed t-test was used within the group analysis in B.

https://doi.org/10.7554/eLife.11290.010
Figure 5—source data 1

Ocular dominance indexes and V1-activation individual values for Figure 5.

https://doi.org/10.7554/eLife.11290.011
Brief inhibition of MMPs after induction of a photothrombotic lesion in S1 rescued experience-enabled enhancements of both the spatial frequency (A) and contrast sensitivity (B) thresholds of the optomotor reflex in adult mice.

Values of vehicle-treated PT-mice are shown in black and values of GM6001-treated mice in grey. Layout and data presentation as in figure 3. Mean ± SEM, ***p<0.001, ns p>0.05. ANOVA followed by multiple comparisons with Bonferroni correction and two-tailed t-test was used in A within the group analysis.

https://doi.org/10.7554/eLife.11290.012
Figure 6—source data 1

Optomotry-measured the spatial frequency and contrast sensitivity individual values for Figure 6.

https://doi.org/10.7554/eLife.11290.013

Tables

Table 1

Optomotry-measured contrast sensitivity improvements after MD

https://doi.org/10.7554/eLife.11290.008
Contrast sensitivity
Day 0
Spatial frequency (cyc/deg)ControlGM6001Control+MDGM6001+MD
0.0313.6 ± 0.043.5 ± 0.023.5 ± 0.013.5 ± 0.01
0.06412.7 ± 0.5211.8 ± 0.1611.6 ± 0.2312.0 ± 0.15
0.09211.7 ± 0.5110.9 ± 0.1810.7 ± 0.2211.3 ± 0.17
0.10310.3 ± 0.5410.2 ± 0.1010.0 ± 0.1610.6 ± 0.12
0.1926.9 ± 0.076.9 ± 0.127.0 ± 0.116.8 ± 0.05
0.2723.5 ± 0.043.5 ± 0.023.5 ± 0.013.5 ± 0.01
Day 7
0.0313.6 ± 0.043.5 ± 0.025.1 ± 0.173.6 ± 0.02
0.06412.7 ± 0.4711.8 ± 0.1826.9 ± 2.3512.6 ± 0.29
0.09211.7 ± 0.4411.0 ± 0.1523.3 ± 2.1712.0 ± 0.22
0.10310.5 ± 0.4910.3 ± 0.1021.8 ± 1.8311.3 ± 0.17
0.1927.0 ± 0.087.0 ± 0.1013.5 ± 1.087.5 ± 0.21
0.2723.5 ± 0.043.5 ± 0.014.9 ± 0.173.8 ± 0.25
Table 2

Optomotry-measured contrast sensitivity improvements after MD

https://doi.org/10.7554/eLife.11290.014
Contrast sensitivity
Day 0
Spatial frequency (cyc/deg)PT+vehiclePT+GM6001PT+MD
vehicle
PT+MD
GM6001
0.0313.5 ± 0.023.5 ± 0.043.5 ± 0.023.5 ± 0.02
0.06411.4 ± 0.3511.4 ± 0.3211.8 ± 0.5711.8 ± 0.15
0.09210.5 ± 0.3610.5 ± 0.3410.7 ± 0.3911.0 ± 0.16
0.1039.8 ± 0.269.9 ± 0.2810.0 ± 0.3710.0 ± 0.32
0.1926.9 ± 0.126.7 ± 0.096.7 ± 0.136.5 ± 0.26
0.2723.5 ± 0.033.5 ± 0.043.4 ± 0.013.5 ± 0.02
Day 7
0.0313.5 ± 0.023.5 ± 0.043.5 ± 0.015.0 ± 0.11
0.06411.4 ± 0.3911.5 ± 0.3212.1 ± 0.4225.2 ± 1.53
0.09210.5 ± 0.3610.5 ± 0.3411.4 ± 0.2821.9. ± 1.14
0.1039.9 ± 0.249.9 ± 0.2810.6 ± 0.2619.7 ± 1.25
0.1926.9 ± 0.116.8 ± 0.077.0 ± 0.0212.8 ± 0.91
0.2723.5 ± 0.023.5 ± 0.043.5 ± 0.024.9 ± 0.12

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