Cited by 170Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsGenetics and Neurodevelopmental Disorders

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Shaping Synapses by the Neural Extracellular Matrix

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Ferrer-Ferrer, Maura, Dityatev, Alexander·2018·Frontiers in Neuroanatomy

DOI 10.3389/fnana.2018.00040PMC PMC5962695

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Abstract

Accumulating data support the importance of interactions between pre- and postsynaptic neuronal elements with astroglial processes and extracellular matrix (ECM) for formation and plasticity of chemical synapses, and thus validate the concept of a tetrapartite synapse. Here we outline the major mechanisms driving: (i) synaptogenesis by secreted extracellular scaffolding molecules, like thrombospondins (TSPs), neuronal pentraxins (NPs) and cerebellins, which respectively promote presynaptic, postsynaptic differentiation or both; (ii) maturation of synapses via reelin and integrin ligands-mediated signaling; and (iii) regulation of synaptic plasticity by ECM-dependent control of induction and consolidation of new synaptic configurations. Particularly, we focused on potential importance of activity-dependent concerted activation of multiple extracellular proteases, such as ADAMTS4/5/15, MMP9 and neurotrypsin, for permissive and instructive events in synaptic remodeling through localized degradation of perisynaptic ECM and generation of proteolytic fragments as inducers of synaptic plasticity.

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Figure 1 Extracellular matrix (ECM) in structural and functional synaptic plasticity. (A) (1) Cerebellin 1 (Cbln1) released from presynaptic neurons binds to its presynaptic α- and β-neurexins (α/βNrxn) receptors and directly recruits postsynaptic GluD2 located on postsynaptic neurons. The tripartite complex induces and maintains excitatory synapses. (2) Neuronal pentraxin 1 and 2 (NP1/2) and neuronal pentraxin receptor (NPR) co-aggregate with GluA4 subunit-containing AMPARs in neurons. Cleavage of NPR by TACE triggers AMPAR endocytosis during LTD. NP1/2 are secreted mainly from the presynaptic side, but where they bind to NPR remains unclear. (3) Integrins are involved in homeostatic synaptic scaling. Pharmacological blockade of action potentials leads to a “scaling up” of the AMPARs present at the synapse. This requires an increase of β3 integrins at the surface, which results in inhibition of the small GTPase Rap1, which normally stimulates the endocytic removal of GluA2-containing AMPARs from the cell surface. As a net outcome, synaptic expression of AMPARs is increased, resulting in larger excitatory postsynaptic currents. This mechanism is most likely negatively regulated by SPARC. (4) Hevin secreted from astrocytes induces synaptogenesis by bridging direct interaction-incompatible Neurexin-1α (Nrx1α) and Neuroligin-1B (NL1B) across the synaptic cleft. SPARC strongly inhibits Hevin-induced excitatory synaptogenesis in vitro. (B) (5) The neuronal serine protease neurotrypsin (NT) is stored in presynaptic terminals and secreted in an inactive form in response to presynaptic action potential (AP) firing. NT contains a pro-domain that inhibits its proteolytic activity. Its activation requires a zymogen activation presumably by a proprotein convertase (PC). Activated neurotrypsin cleaves agrin and yields a C-terminal 22-kDa fragment (Ag22), which inhibits the α3 subunit of the Na+/K+ ATPase (α3NKA) and induces dendritic filopodia formation. (6) Reelin signals through its receptors, very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (APOER2), which interact with adaptor protein disabled 1 (Dab1). Activation of reelin signaling pathway results in cytoplasmic adaptor protein disabled 1 (Dab1) phosphorylation via the Src family of tyrosine kinases (SFK), activation of SFKs and tyrosine phosphorylation of NMDARs that increases receptor activity. This mechanism induces LTP and spinogenesis and it is negatively regulated by ADAMTS dependent reelin cleavage. (7) Hyaluronic acid and tenascin-C support the activity of neuronal L-type voltage-gated Ca2+ channels (LVGCCs). Ca2+ influx through NMDARs and LGCCs induces diverse forms of LTP.CC BY · PubMed Central

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Authors: Ferrer-Ferrer, M., & Dityatev, A.
Affiliations: German Center for Neurodegenerative Diseases (DE)
Corresponding author: Dityatev, Alexander
ORCID: Dityatev, Alexander
Venue: Frontiers in Neuroanatomy
Publisher: Frontiers Media SA
Published: 2018-05-15
Volume: 12
Pages: 40-40
ISSN: 1662-5129 (ISSN-L)
DOI: 10.3389/fnana.2018.00040
PMC: PMC5962695
OpenAlex: W2804637583
Cited by: 169
References: 222
Citations by year: 2026: 11 · 2025: 16 · 2024: 18 · 2023: 19 · 2022: 26 · 2021: 34 · 2020: 19 · 2019: 21 · 2018: 5
FWCI: 2.59
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: Frontiers in Neuroanatomy (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
DZNE Pub (submittedVersion, cc-by)
Funders: Seventh Framework Programme (Initial Training Network ExtraBrain)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: synaptogenesis, synaptic plasticity, thrombospondin, cerebellin, reelin, integrin signaling, extracellular protease, ADAMTS, MMP-9, synaptic remodeling

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Shaping Synapses by the Neural Extracellular Matrix

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