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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

Synapse Density but not postsynaptic density (PSD) size is affected in MMP9 KO mice. Representative examples of images obtained from CTL ND (A) and MMP9 KO ND (B) visual cortex following pre-embedding electron microscopy ultra-structural preparation for synaptic profiling. Images show the appearance of asymmetric (excitatory; glutamatergic) synapses (denoted by +) abutting presynaptic terminals containing neurotransmitter vesicles (denoted by t). (C) Quantitative analysis of the total number of asymmetrical synapses in CTL ND (black bar) vs. MMP9 KO ND (white bar) showing a significant decrease in MMP9 KO synapses. (D) Examples of PSD length measurements performed using Image J software in CTL ND (first panel) and MMP9 KO ND (second panel). (E) Quantitative analysis of PSD lengths in CTL ND (black bar) and MMP9 KO ND (white bar). No significant difference was observed. Scale bars = 200 nm (A,B); 250 nm (D). Statistics = Students t-test. All values reported are the mean ± SEM. *p < 0.05.
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Figure 6: Synapse Density but not postsynaptic density (PSD) size is affected in MMP9 KO mice. Representative examples of images obtained from CTL ND (A) and MMP9 KO ND (B) visual cortex following pre-embedding electron microscopy ultra-structural preparation for synaptic profiling. Images show the appearance of asymmetric (excitatory; glutamatergic) synapses (denoted by +) abutting presynaptic terminals containing neurotransmitter vesicles (denoted by t). (C) Quantitative analysis of the total number of asymmetrical synapses in CTL ND (black bar) vs. MMP9 KO ND (white bar) showing a significant decrease in MMP9 KO synapses. (D) Examples of PSD length measurements performed using Image J software in CTL ND (first panel) and MMP9 KO ND (second panel). (E) Quantitative analysis of PSD lengths in CTL ND (black bar) and MMP9 KO ND (white bar). No significant difference was observed. Scale bars = 200 nm (A,B); 250 nm (D). Statistics = Students t-test. All values reported are the mean ± SEM. *p < 0.05.

Mentions: MMP9 and the ECM can regulate the structure of dendritic spines, the postsynaptic sites of excitatory synapses, (Szklarczyk et al., 2002; Ethell and Ethell, 2007), and dynamic changes in dendritic spine structure accompany ODP (Oray et al., 2004). To ascertain whether changes in ECM composition in MMP9 KO mice may differentially regulate cortical excitatory synapses and thus affect plasticity, we used electron microscopy to quantify asymmetric synapse density (Figures 6A–C) and PSD size (Figure 6D) in layer 2 of visual cortex. We found that MMP9 KO mice had significantly fewer asymmetric synapses in the same cortical area when compared to CTL mice (Figure 6C). This change in synaptic density was not accompanied by changes in PSD size (Figure 6E). These data suggest that deficits in excitatory synapse development may contribute to the plasticity phenotype observed in MMP9 KO mice, and that synaptic density rather than synaptic strength may be affected.


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)

Synapse Density but not postsynaptic density (PSD) size is affected in MMP9 KO mice. Representative examples of images obtained from CTL ND (A) and MMP9 KO ND (B) visual cortex following pre-embedding electron microscopy ultra-structural preparation for synaptic profiling. Images show the appearance of asymmetric (excitatory; glutamatergic) synapses (denoted by +) abutting presynaptic terminals containing neurotransmitter vesicles (denoted by t). (C) Quantitative analysis of the total number of asymmetrical synapses in CTL ND (black bar) vs. MMP9 KO ND (white bar) showing a significant decrease in MMP9 KO synapses. (D) Examples of PSD length measurements performed using Image J software in CTL ND (first panel) and MMP9 KO ND (second panel). (E) Quantitative analysis of PSD lengths in CTL ND (black bar) and MMP9 KO ND (white bar). No significant difference was observed. Scale bars = 200 nm (A,B); 250 nm (D). Statistics = Students t-test. All values reported are the mean ± SEM. *p < 0.05.
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Related In: Results  -  Collection

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Show All Figures
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Figure 6: Synapse Density but not postsynaptic density (PSD) size is affected in MMP9 KO mice. Representative examples of images obtained from CTL ND (A) and MMP9 KO ND (B) visual cortex following pre-embedding electron microscopy ultra-structural preparation for synaptic profiling. Images show the appearance of asymmetric (excitatory; glutamatergic) synapses (denoted by +) abutting presynaptic terminals containing neurotransmitter vesicles (denoted by t). (C) Quantitative analysis of the total number of asymmetrical synapses in CTL ND (black bar) vs. MMP9 KO ND (white bar) showing a significant decrease in MMP9 KO synapses. (D) Examples of PSD length measurements performed using Image J software in CTL ND (first panel) and MMP9 KO ND (second panel). (E) Quantitative analysis of PSD lengths in CTL ND (black bar) and MMP9 KO ND (white bar). No significant difference was observed. Scale bars = 200 nm (A,B); 250 nm (D). Statistics = Students t-test. All values reported are the mean ± SEM. *p < 0.05.
Mentions: MMP9 and the ECM can regulate the structure of dendritic spines, the postsynaptic sites of excitatory synapses, (Szklarczyk et al., 2002; Ethell and Ethell, 2007), and dynamic changes in dendritic spine structure accompany ODP (Oray et al., 2004). To ascertain whether changes in ECM composition in MMP9 KO mice may differentially regulate cortical excitatory synapses and thus affect plasticity, we used electron microscopy to quantify asymmetric synapse density (Figures 6A–C) and PSD size (Figure 6D) in layer 2 of visual cortex. We found that MMP9 KO mice had significantly fewer asymmetric synapses in the same cortical area when compared to CTL mice (Figure 6C). This change in synaptic density was not accompanied by changes in PSD size (Figure 6E). These data suggest that deficits in excitatory synapse development may contribute to the plasticity phenotype observed in MMP9 KO mice, and that synaptic density rather than synaptic strength may be affected.

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