Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.
Perineuronal nets (PNNs) are condensed extracellular matrix structures that surround the soma and proximal dendrites of some classes of neurons . In the brain, these are particularly GABAergic parvalbumin+ (PV+) interneurons. PNNs surround synapses and are involved in the control of developmental and adult plasticity [2,3,4,5,6]. PNNs are formed via hierarchical assembly of various chondroitin sulphate proteoglycans (CSPGs), hyaluronan, tenascin-R, hyaluronan and proteoglycan link proteins (haplns) and other PNN-associated extracellular matrix (ECM) molecules such as semaphorin 3 A [7,8,9,10,11]. Their ability to control plasticity depends on the sulphated chondroitin sulphate glycosaminoglycan chains (CS-GAGs) of the CSPGs [12, 13].