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Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice.

Kelly EA, Russo AS, Jackson CD, Lamantia CE, Majewska AK - Front Cell Neurosci (2015)

Bottom Line: Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex.We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity.Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9.

View Article: PubMed Central - PubMed

Affiliation: Center for Visual Science, School of Medicine and Dentistry, Department of Neurobiology and Anatomy, University of Rochester Rochester, NY, USA.

ABSTRACT
The extracellular matrix (ECM) is known to play important roles in regulating neuronal recovery from injury. The ECM can also impact physiological synaptic plasticity, although this process is less well understood. To understand the impact of the ECM on synaptic function and remodeling in vivo, we examined ECM composition and proteolysis in a well-established model of experience-dependent plasticity in the visual cortex. We describe a rapid change in ECM protein composition during Ocular Dominance Plasticity (ODP) in adolescent mice, and a loss of ECM remodeling in mice that lack the extracellular protease, matrix metalloproteinase-9 (MMP9). Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex. While we observed no change in the morphology of existing dendritic spines, spine dynamics were altered, and MMP9 knock-out (KO) mice showed increased turnover of dendritic spines over a period of 2 days. We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity. MMP9 KO mice exhibited very limited changes in microglial morphology. Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9. Taken together, our results show that MMP9 contributes to ECM degradation, synaptic dynamics and sensory-evoked plasticity in the mouse visual cortex.

No MeSH data available.


Related in: MedlinePlus

Dendritic spine turnover is altered in MMP9 KO mice. (A) Example of thin skull preparation viewed through dissecting scope showing clear demarcation of brain vasculature. (B) Magnified epifluorescent image of the region of interest (ROI, hatched box in (A)) visualized with a 20 × 0.95 NA objective lens. Vasculature landmarks aided in relocating ROI in chronic imaging. (C) Two-photon image of the same region (as A and B) taken at 1× digital zoom which served as a reference map of magnified vessels and dendritic branches. (D) 8x digital zoom of dendritic branches and spines on D0 (first panel) and identical branches at D2 (second panel). Asterisks (d*) denote reference spines between images. L = lost spines, N = new spines. (E) Quantitative analysis of percent dendritic spine turnover in CTL ND (black bars) and MMP9 KO ND (white bars) mice. CTL ND mice showed significantly more lost spines than gained spines after 2 days (Two-Way ANOVA, *p < 0.05). Spine loss and gain were not significantly different in MMP9 KO ND mice. Scale bar = 200 μm (A–C), 5 μm (D). All values reported are the mean ± SEM.
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Figure 8: Dendritic spine turnover is altered in MMP9 KO mice. (A) Example of thin skull preparation viewed through dissecting scope showing clear demarcation of brain vasculature. (B) Magnified epifluorescent image of the region of interest (ROI, hatched box in (A)) visualized with a 20 × 0.95 NA objective lens. Vasculature landmarks aided in relocating ROI in chronic imaging. (C) Two-photon image of the same region (as A and B) taken at 1× digital zoom which served as a reference map of magnified vessels and dendritic branches. (D) 8x digital zoom of dendritic branches and spines on D0 (first panel) and identical branches at D2 (second panel). Asterisks (d*) denote reference spines between images. L = lost spines, N = new spines. (E) Quantitative analysis of percent dendritic spine turnover in CTL ND (black bars) and MMP9 KO ND (white bars) mice. CTL ND mice showed significantly more lost spines than gained spines after 2 days (Two-Way ANOVA, *p < 0.05). Spine loss and gain were not significantly different in MMP9 KO ND mice. Scale bar = 200 μm (A–C), 5 μm (D). All values reported are the mean ± SEM.

Mentions: Alterations in spine density may be the result of aberrant spine formation or elimination. To determine if spine dynamics are affected by MMP9 deficiency, we investigated dendritic spine turnover in GFP-M CTL mice and MMP9 KO GFP in vivo using chronic two-photon (2P) imaging. The skull over S1 was thinned to reveal the cortical vasculature (Figures 8A–C) which was used as a reference for chronic imaging. Dendritic spines from the apical tufts of L5 pyramidal neurons were imaged on D0 (first day imaging, P28) and the same spines were reimaged 2 days later (D2) (Figure 8D). Under basal conditions (CTL ND), CTL GFP-M mice displayed a significantly greater rate of spine loss compared to spine gain (Figure 8E, black bars, p < 0.05), as has previously been described during adolescence (Zuo et al., 2005). This effect was not seen in mice lacking MMP9, where loss and gain rates were well matched (Figure 8E, white bars). These results suggest that spine dynamics are altered in MMP9 KO mice.


Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice.

Kelly EA, Russo AS, Jackson CD, Lamantia CE, Majewska AK - Front Cell Neurosci (2015)

Dendritic spine turnover is altered in MMP9 KO mice. (A) Example of thin skull preparation viewed through dissecting scope showing clear demarcation of brain vasculature. (B) Magnified epifluorescent image of the region of interest (ROI, hatched box in (A)) visualized with a 20 × 0.95 NA objective lens. Vasculature landmarks aided in relocating ROI in chronic imaging. (C) Two-photon image of the same region (as A and B) taken at 1× digital zoom which served as a reference map of magnified vessels and dendritic branches. (D) 8x digital zoom of dendritic branches and spines on D0 (first panel) and identical branches at D2 (second panel). Asterisks (d*) denote reference spines between images. L = lost spines, N = new spines. (E) Quantitative analysis of percent dendritic spine turnover in CTL ND (black bars) and MMP9 KO ND (white bars) mice. CTL ND mice showed significantly more lost spines than gained spines after 2 days (Two-Way ANOVA, *p < 0.05). Spine loss and gain were not significantly different in MMP9 KO ND mice. Scale bar = 200 μm (A–C), 5 μm (D). All values reported are the mean ± SEM.
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Figure 8: Dendritic spine turnover is altered in MMP9 KO mice. (A) Example of thin skull preparation viewed through dissecting scope showing clear demarcation of brain vasculature. (B) Magnified epifluorescent image of the region of interest (ROI, hatched box in (A)) visualized with a 20 × 0.95 NA objective lens. Vasculature landmarks aided in relocating ROI in chronic imaging. (C) Two-photon image of the same region (as A and B) taken at 1× digital zoom which served as a reference map of magnified vessels and dendritic branches. (D) 8x digital zoom of dendritic branches and spines on D0 (first panel) and identical branches at D2 (second panel). Asterisks (d*) denote reference spines between images. L = lost spines, N = new spines. (E) Quantitative analysis of percent dendritic spine turnover in CTL ND (black bars) and MMP9 KO ND (white bars) mice. CTL ND mice showed significantly more lost spines than gained spines after 2 days (Two-Way ANOVA, *p < 0.05). Spine loss and gain were not significantly different in MMP9 KO ND mice. Scale bar = 200 μm (A–C), 5 μm (D). All values reported are the mean ± SEM.
Mentions: Alterations in spine density may be the result of aberrant spine formation or elimination. To determine if spine dynamics are affected by MMP9 deficiency, we investigated dendritic spine turnover in GFP-M CTL mice and MMP9 KO GFP in vivo using chronic two-photon (2P) imaging. The skull over S1 was thinned to reveal the cortical vasculature (Figures 8A–C) which was used as a reference for chronic imaging. Dendritic spines from the apical tufts of L5 pyramidal neurons were imaged on D0 (first day imaging, P28) and the same spines were reimaged 2 days later (D2) (Figure 8D). Under basal conditions (CTL ND), CTL GFP-M mice displayed a significantly greater rate of spine loss compared to spine gain (Figure 8E, black bars, p < 0.05), as has previously been described during adolescence (Zuo et al., 2005). This effect was not seen in mice lacking MMP9, where loss and gain rates were well matched (Figure 8E, white bars). These results suggest that spine dynamics are altered in MMP9 KO mice.

Bottom Line: Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex.We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity.Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9.

View Article: PubMed Central - PubMed

Affiliation: Center for Visual Science, School of Medicine and Dentistry, Department of Neurobiology and Anatomy, University of Rochester Rochester, NY, USA.

ABSTRACT
The extracellular matrix (ECM) is known to play important roles in regulating neuronal recovery from injury. The ECM can also impact physiological synaptic plasticity, although this process is less well understood. To understand the impact of the ECM on synaptic function and remodeling in vivo, we examined ECM composition and proteolysis in a well-established model of experience-dependent plasticity in the visual cortex. We describe a rapid change in ECM protein composition during Ocular Dominance Plasticity (ODP) in adolescent mice, and a loss of ECM remodeling in mice that lack the extracellular protease, matrix metalloproteinase-9 (MMP9). Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex. While we observed no change in the morphology of existing dendritic spines, spine dynamics were altered, and MMP9 knock-out (KO) mice showed increased turnover of dendritic spines over a period of 2 days. We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity. MMP9 KO mice exhibited very limited changes in microglial morphology. Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9. Taken together, our results show that MMP9 contributes to ECM degradation, synaptic dynamics and sensory-evoked plasticity in the mouse visual cortex.

No MeSH data available.


Related in: MedlinePlus