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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

Agrin cleavage by neurotrypsin plays an important role in filopodia formation following LTP. In wild type animals after an LTP stimulus, agrin is cleaved by neurotrypsin (top left) and the agrin fragment promotes growth of new dendritic filopodia (top right). In neurotrypsin knockout mice, agrin cannot be cleaved (bottom left) and new filopodia are not formed in response to an LTP-inducing stimulus (bottom right). However, application of a soluble recombinant neurotrypsin-dependent agrin cleavage fragment rescues this phenotype, promoting new filopodia growth after LTP even in neurotrypsin knockout hippocampal slices. See Matsumoto-Miyai et al. (2009).
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Figure 4: Agrin cleavage by neurotrypsin plays an important role in filopodia formation following LTP. In wild type animals after an LTP stimulus, agrin is cleaved by neurotrypsin (top left) and the agrin fragment promotes growth of new dendritic filopodia (top right). In neurotrypsin knockout mice, agrin cannot be cleaved (bottom left) and new filopodia are not formed in response to an LTP-inducing stimulus (bottom right). However, application of a soluble recombinant neurotrypsin-dependent agrin cleavage fragment rescues this phenotype, promoting new filopodia growth after LTP even in neurotrypsin knockout hippocampal slices. See Matsumoto-Miyai et al. (2009).

Mentions: A role for agrin in spine and synapse stability is also supported by studies of neurotrypsin (also called motopsin or Prss12), an extracellular protease whose only known substrate is agrin (Gschwend et al., 1997; Molinari et al., 2002; Reif et al., 2007; Stephan et al., 2008). neurotrypsin−/− mice have reduced CA1 apical dendritic spine density (Mitsui et al., 2009). Neurotrypsin is released from presynaptic neurons in response to NMDAR-mediated activity and cleaves agrin at the synapse, suggesting that neurotrypsin might be involved in activity-dependent plasticity. Indeed, while neurons in hippocampal slices from adult neurotrypsin−/− mice have normal electrophysiological LTP, LTP-inducing stimuli fail to induce the formation of new filopodia in the knockouts, suggesting that neurotrypsin is required for some aspects of structural plasticity that accompany LTP in adult animals. Interestingly, a soluble cleavage fragment of agrin produced by neurotrypsin can rescue the loss of LTP-induced filopodia formation in neurotrypsin−/− mice (Matsumoto-Miyai et al., 2009; Figure 4). These results suggest a role for neurotrypsin and agrin in supporting new spine formation following LTP induction protocols in mature animals. Further work should address the molecular mechanisms downstream of agrin cleavage that promote filopodia formation and whether and how these new filopodia form functional dendritic spines and synapses.


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

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

Agrin cleavage by neurotrypsin plays an important role in filopodia formation following LTP. In wild type animals after an LTP stimulus, agrin is cleaved by neurotrypsin (top left) and the agrin fragment promotes growth of new dendritic filopodia (top right). In neurotrypsin knockout mice, agrin cannot be cleaved (bottom left) and new filopodia are not formed in response to an LTP-inducing stimulus (bottom right). However, application of a soluble recombinant neurotrypsin-dependent agrin cleavage fragment rescues this phenotype, promoting new filopodia growth after LTP even in neurotrypsin knockout hippocampal slices. See Matsumoto-Miyai et al. (2009).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Agrin cleavage by neurotrypsin plays an important role in filopodia formation following LTP. In wild type animals after an LTP stimulus, agrin is cleaved by neurotrypsin (top left) and the agrin fragment promotes growth of new dendritic filopodia (top right). In neurotrypsin knockout mice, agrin cannot be cleaved (bottom left) and new filopodia are not formed in response to an LTP-inducing stimulus (bottom right). However, application of a soluble recombinant neurotrypsin-dependent agrin cleavage fragment rescues this phenotype, promoting new filopodia growth after LTP even in neurotrypsin knockout hippocampal slices. See Matsumoto-Miyai et al. (2009).
Mentions: A role for agrin in spine and synapse stability is also supported by studies of neurotrypsin (also called motopsin or Prss12), an extracellular protease whose only known substrate is agrin (Gschwend et al., 1997; Molinari et al., 2002; Reif et al., 2007; Stephan et al., 2008). neurotrypsin−/− mice have reduced CA1 apical dendritic spine density (Mitsui et al., 2009). Neurotrypsin is released from presynaptic neurons in response to NMDAR-mediated activity and cleaves agrin at the synapse, suggesting that neurotrypsin might be involved in activity-dependent plasticity. Indeed, while neurons in hippocampal slices from adult neurotrypsin−/− mice have normal electrophysiological LTP, LTP-inducing stimuli fail to induce the formation of new filopodia in the knockouts, suggesting that neurotrypsin is required for some aspects of structural plasticity that accompany LTP in adult animals. Interestingly, a soluble cleavage fragment of agrin produced by neurotrypsin can rescue the loss of LTP-induced filopodia formation in neurotrypsin−/− mice (Matsumoto-Miyai et al., 2009; Figure 4). These results suggest a role for neurotrypsin and agrin in supporting new spine formation following LTP induction protocols in mature animals. Further work should address the molecular mechanisms downstream of agrin cleavage that promote filopodia formation and whether and how these new filopodia form functional dendritic spines and synapses.

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