Animals lacking link protein have attenuated perineuronal nets and persistent plasticity

Abstract

Chondroitin sulphate proteoglycans in the extracellular matrix restrict plasticity in the adult central nervous system and their digestion with chondroitinase reactivates plasticity. However the structures in the extracellular matrix that restrict plasticity are unknown. There are many changes in the extracellular matrix as critical periods for plasticity close, including changes in chondroitin sulphate proteoglycan core protein levels, changes in glycosaminoglycan sulphation and the appearance of dense chondroitin sulphate proteoglycan-containing perineuronal nets around many neurons. We show that formation of perineuronal nets is triggered by neuronal production of cartilage link protein Crtl1 (Hapln1), which is up-regulated in the visual cortex as perineuronal nets form during development and after dark rearing. Mice lacking Crtl1 have attenuated perineuronal nets, but the overall levels of chondroitin sulphate proteoglycans and their pattern of glycan sulphation are unchanged. Crtl1 knockout animals retain juvenile levels of ocular dominance plasticity and their visual acuity remains sensitive to visual deprivation. In the sensory pathway, axons in knockout animals but not controls sprout into the party denervated cuneate nucleus. The organization of chondroitin sulphate proteoglycan into perineuronal nets is therefore the key event in the control of central nervous system plasticity by the extracellular matrix.

Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains

“…3A). We have previously demonstrated that the PNN GAG fraction contains ϳ70% CS and ϳ30% HS (9). To examine if the binding is due to the presence of CS or HS, we treated the GAG solution with ChABC, heparitinases I and III, or a combination of the enzymes in a competitive ELISA.…”

“…They contain aggrecan, neurocan, versican, and brevican, which are CSPGs from the lectican family, and phosphacan, a surface-bound CSPG. The lecticans interact with hyaluronan via their N-terminal link modules, and the interactions are further stabilized by one or both of the link proteins, cartilage link protein (Crtl1), and brain link protein 2 (Bral2) (3,4,9). The C terminus of the CSPGs also binds to tenascin-R, producing a stable ternary structure.…”

“…Degradation of CS by enzymatic treatment using chondroitinase ABC (ChABC) has demonstrated remarkable enhancement in plasticity in the visual cortex (8) and in the injured CNS (11)(12)(13) and prolongation of memory (14). The same enhancement of plasticity and memory is also observed in animals that lack Crtl1 in the CNS and therefore have attenuated PNNs, indicating that ChABC promotes plasticity through digestion of CS-GAGs in PNNs (9).…”

Perineuronal nets protect fast-spiking interneurons against oxidative stress

“…When most fast-spiking PV cells mature (30), they become enwrapped by a specialized extracellular matrix or aggrecan-enriched perineuronal nets (PNNs). These PNNs consist of highly charged chondroitin sulfate proteoglycans (e.g., aggrecan, neurocan, brevican), hyaluronan, tenascin, and link proteins (31). The PNNs promote interneuron maturation and synaptic and network stability (reviewed in refs.…”

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

“…The direct link with plasticity is stressed by the activity-regulated maturation of EM [5][6][7] ending in parallel with the closure of the juvenile critical period of heightened plasticity 6,8 . The relationship between critical period closure and EM is reciprocal, as alterations of the EM structure prolong the critical period 9,10 and plasticity processes can be partially restored in the adult brain by degradation of the EM [11][12][13][14][15] . Key components of the extracellular environment are the chondroitin sulfate proteoglycans (CSPGs): these molecules are formed by a proteic scaffold supporting chondroitin sulfate glycosaminoglycan chains.…”