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Extracellular matrix control of dendritic spine and synapse structure and plasticity in adulthood.

Levy AD, Omar MH, Koleske AJ - Front Neuroanat (2014)

Bottom Line: The extracellular matrix (ECM), composed of a meshwork of proteins and proteoglycans, is a critical regulator of spine and synapse stability and plasticity.While the role of ECM receptors in spine regulation has been extensively studied, considerably less research has focused directly on the role of specific ECM ligands.Here, we review the evidence for a role of several brain ECM ligands and remodeling proteases in the regulation of dendritic spine and synapse formation, plasticity, and stability in adults.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Neuroscience Program, Yale University New Haven, CT, USA ; Department of Molecular Biophysics and Biochemistry, Yale University New Haven, CT, USA.

ABSTRACT
Dendritic spines are the receptive contacts at most excitatory synapses in the central nervous system. Spines are dynamic in the developing brain, changing shape as they mature as well as appearing and disappearing as they make and break connections. Spines become much more stable in adulthood, and spine structure must be actively maintained to support established circuit function. At the same time, adult spines must retain some plasticity so their structure can be modified by activity and experience. As such, the regulation of spine stability and remodeling in the adult animal is critical for normal function, and disruption of these processes is associated with a variety of late onset diseases including schizophrenia and Alzheimer's disease. The extracellular matrix (ECM), composed of a meshwork of proteins and proteoglycans, is a critical regulator of spine and synapse stability and plasticity. While the role of ECM receptors in spine regulation has been extensively studied, considerably less research has focused directly on the role of specific ECM ligands. Here, we review the evidence for a role of several brain ECM ligands and remodeling proteases in the regulation of dendritic spine and synapse formation, plasticity, and stability in adults.

No MeSH data available.


Related in: MedlinePlus

Matrix metalloproteinases play diverse roles in dendritic spine remodeling in disease, development, and plasticity. (A) In Fragile X syndrome (FXS), MMP9 is hyperactive and dendritic spines are elongated early in development. MMP9 loss of function or inhibition with minocycline normalizes these spine defects. In epilepsy models, seizure-induced spine loss is blocked by inhibition of MMP activity. (B) In development, activation of MMPs, particularly MMP9, causes spine thinning and elongation, while MMP inhibition promotes the maturation of filopodia into mature, mushroom shaped spines. (C) Matrix metalloproteinases play a different role in adult plasticity, cleaving unknown ECM proteins to reveal cryptic integrin ligands that drive spine enlargement during LTP. In addition to changes in spine size, MMP activity is required for the maintenance phase of LTP.
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Figure 5: Matrix metalloproteinases play diverse roles in dendritic spine remodeling in disease, development, and plasticity. (A) In Fragile X syndrome (FXS), MMP9 is hyperactive and dendritic spines are elongated early in development. MMP9 loss of function or inhibition with minocycline normalizes these spine defects. In epilepsy models, seizure-induced spine loss is blocked by inhibition of MMP activity. (B) In development, activation of MMPs, particularly MMP9, causes spine thinning and elongation, while MMP inhibition promotes the maturation of filopodia into mature, mushroom shaped spines. (C) Matrix metalloproteinases play a different role in adult plasticity, cleaving unknown ECM proteins to reveal cryptic integrin ligands that drive spine enlargement during LTP. In addition to changes in spine size, MMP activity is required for the maintenance phase of LTP.

Mentions: MMP9 activity is also important in another pathophysiological condition, Fragile X syndrome (FXS). Mice with FXS have more long and thin spines than wild type mice, especially early in development. Treatment of FXS mice or hippocampal cultures derived from these mice with minocycline to inhibit MMP9 can normalize spine morphology (Bilousova et al., 2009), suggesting that hyperactive MMP9 in development prevents spine maturation. Indeed, MMP9 has recently been shown directly to be hyperactive in FXS mice, and disruption of the MMP9 gene in FXS mice normalizes the spine, behavioral, and signal transduction defects associated with FXS (Sidhu et al., 2014). These results demonstrate that pathophysiological activation of MMP9 can promote changes in dendritic spine morphology associated with disease (Figure 5A).


Extracellular matrix control of dendritic spine and synapse structure and plasticity in adulthood.

Levy AD, Omar MH, Koleske AJ - Front Neuroanat (2014)

Matrix metalloproteinases play diverse roles in dendritic spine remodeling in disease, development, and plasticity. (A) In Fragile X syndrome (FXS), MMP9 is hyperactive and dendritic spines are elongated early in development. MMP9 loss of function or inhibition with minocycline normalizes these spine defects. In epilepsy models, seizure-induced spine loss is blocked by inhibition of MMP activity. (B) In development, activation of MMPs, particularly MMP9, causes spine thinning and elongation, while MMP inhibition promotes the maturation of filopodia into mature, mushroom shaped spines. (C) Matrix metalloproteinases play a different role in adult plasticity, cleaving unknown ECM proteins to reveal cryptic integrin ligands that drive spine enlargement during LTP. In addition to changes in spine size, MMP activity is required for the maintenance phase of LTP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4202714&req=5

Figure 5: Matrix metalloproteinases play diverse roles in dendritic spine remodeling in disease, development, and plasticity. (A) In Fragile X syndrome (FXS), MMP9 is hyperactive and dendritic spines are elongated early in development. MMP9 loss of function or inhibition with minocycline normalizes these spine defects. In epilepsy models, seizure-induced spine loss is blocked by inhibition of MMP activity. (B) In development, activation of MMPs, particularly MMP9, causes spine thinning and elongation, while MMP inhibition promotes the maturation of filopodia into mature, mushroom shaped spines. (C) Matrix metalloproteinases play a different role in adult plasticity, cleaving unknown ECM proteins to reveal cryptic integrin ligands that drive spine enlargement during LTP. In addition to changes in spine size, MMP activity is required for the maintenance phase of LTP.
Mentions: MMP9 activity is also important in another pathophysiological condition, Fragile X syndrome (FXS). Mice with FXS have more long and thin spines than wild type mice, especially early in development. Treatment of FXS mice or hippocampal cultures derived from these mice with minocycline to inhibit MMP9 can normalize spine morphology (Bilousova et al., 2009), suggesting that hyperactive MMP9 in development prevents spine maturation. Indeed, MMP9 has recently been shown directly to be hyperactive in FXS mice, and disruption of the MMP9 gene in FXS mice normalizes the spine, behavioral, and signal transduction defects associated with FXS (Sidhu et al., 2014). These results demonstrate that pathophysiological activation of MMP9 can promote changes in dendritic spine morphology associated with disease (Figure 5A).

Bottom Line: The extracellular matrix (ECM), composed of a meshwork of proteins and proteoglycans, is a critical regulator of spine and synapse stability and plasticity.While the role of ECM receptors in spine regulation has been extensively studied, considerably less research has focused directly on the role of specific ECM ligands.Here, we review the evidence for a role of several brain ECM ligands and remodeling proteases in the regulation of dendritic spine and synapse formation, plasticity, and stability in adults.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Neuroscience Program, Yale University New Haven, CT, USA ; Department of Molecular Biophysics and Biochemistry, Yale University New Haven, CT, USA.

ABSTRACT
Dendritic spines are the receptive contacts at most excitatory synapses in the central nervous system. Spines are dynamic in the developing brain, changing shape as they mature as well as appearing and disappearing as they make and break connections. Spines become much more stable in adulthood, and spine structure must be actively maintained to support established circuit function. At the same time, adult spines must retain some plasticity so their structure can be modified by activity and experience. As such, the regulation of spine stability and remodeling in the adult animal is critical for normal function, and disruption of these processes is associated with a variety of late onset diseases including schizophrenia and Alzheimer's disease. The extracellular matrix (ECM), composed of a meshwork of proteins and proteoglycans, is a critical regulator of spine and synapse stability and plasticity. While the role of ECM receptors in spine regulation has been extensively studied, considerably less research has focused directly on the role of specific ECM ligands. Here, we review the evidence for a role of several brain ECM ligands and remodeling proteases in the regulation of dendritic spine and synapse formation, plasticity, and stability in adults.

No MeSH data available.


Related in: MedlinePlus