title: Perisynaptic chondroitin sulfate proteoglycans restrict structural plasticity in an integrin-dependent manner.
abstract: During early postnatal development of the CNS, neuronal networks are configured through the formation, elimination, and remodeling of dendritic spines, the sites of most excitatory synaptic connections. The closure of this critical period for plasticity correlates with the maturation of the extracellular matrix (ECM) and results in reduced dendritic spine dynamics. Chondroitin sulfate proteoglycans (CSPGs) are thought to be the active components of the mature ECM that inhibit functional plasticity in the adult CNS. These molecules are diffusely expressed in the extracellular space or aggregated as perineuronal nets around specific classes of neurons. We used organotypic hippocampal slices prepared from 6-d-old Thy1-YFP mice and maintained in culture for 4 weeks to allow ECM maturation. We performed live imaging of CA1 pyramidal cells to assess the effect of chondroitinase ABC (ChABC)-mediated digestion of CSPGs on dendritic spine dynamics. We found that CSPG digestion enhanced the motility of dendritic spines and induced the appearance of spine head protrusions in a glutamate receptor-independent manner. These changes were paralleled by the activation of β1-integrins and phosphorylation of focal adhesion kinase at synaptic sites, and were prevented by preincubation with a β1-integrin blocking antibody. Interestingly, microinjection of ChABC close to dendritic segments was sufficient to induce spine remodeling, demonstrating that CSPGs located around dendritic spines modulate their dynamics independently of perineuronal nets. This restrictive action of perisynaptic CSPGs in mature neural tissue may account for the therapeutic effects of ChABC in promoting functional recovery in impaired neural circuits.
authors.affiliation: Brain Research Institute, University of Zürich/Eidgenössische Technische Hochschule, 8057 Zürich, Switzerland.
authors.forename: Clara
authors.initials: C
authors.lastname: Orlando
authors.forename: Jeanne
authors.initials: J
authors.lastname: Ster
authors.forename: Urs
authors.initials: U
authors.lastname: Gerber
authors.forename: James W
authors.initials: JW
authors.lastname: Fawcett
authors.forename: Olivier
authors.initials: O
authors.lastname: Raineteau
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000502:physiology / Q000648:ultrastructure; D019765:Chondroitin ABC Lyase / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D049229:Dendritic Spines / Q000502:physiology* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009473:Neuronal Plasticity / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology / Q000648:ultrastructure
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D019012:Integrin beta1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019765:Chondroitin ABC Lyase