Abstract
Chondroitin sulfate (CS) proteoglycans in perineuronal nets (PNNs) from the central nervous system (CNS) are involved in the control of plasticity and memory. Removing PNNs reactivates plasticity and restores memory in models of Alzheimer’s disease and ageing. Their actions depend on the glycosaminoglycan (GAG) chains of CS proteoglycans, which are mainly sulfated in the 4 (C4S) or 6 (C6S) positions. While C4S is inhibitory, C6S is more permissive to axon growth, regeneration and plasticity. C6S decreases during critical period closure. We asked whether there is a late change in CS-GAG sulfation associated with memory loss in aged rats. Immunohistochemistry revealed a progressive increase in C4S and decrease in C6S from 3 to 18 months. GAGs extracted from brain PNNs showed a large reduction in C6S at 12 and 18 months, increasing the C4S/C6S ratio. There was no significant change in mRNA levels of the chondroitin sulfotransferases. PNN GAGs were more inhibitory to axon growth than those from the diffuse extracellular matrix. The 18-month PNN GAGs were more inhibitory than 3-month PNN GAGs. We suggest that the change in PNN GAG sulfation in aged brains renders the PNNs more inhibitory, which lead to a decrease in plasticity and adversely affect memory.
Highlights
Plasticity in the nervous system declines during ageing, as demonstrated by the progressive reduction in the ability of the central nervous system (CNS) to learn, to adapt to the changing environment and to compensate for damage
Our hypothesis was that the decline in memory and plasticity in the ageing brain might be explained or correlated with changes in the brain extracellular matrix (ECM), in the matrix composing perineuronal nets (PNNs)
We have examined ageing changes in the Chondroitin sulfate (CS)-GAGs because these sulfated chains are critically involved in determining the function of PNNs and in the control of memory and plasticity
Summary
Plasticity in the nervous system declines during ageing, as demonstrated by the progressive reduction in the ability of the central nervous system (CNS) to learn, to adapt to the changing environment and to compensate for damage. An outcome from this change in rodents is a progressive memory deficit detectable from around 12 months [1] (and Yang et al unpublished observations). PNNs are specialized forms of ECM that condense around the surface of neurons at the end of the critical period, surrounding the synapses and blocking new synapse formation [6,7,8,9,10]. CS-GAGs in PNNs constitute 2% of total brain CS-GAG, and the other 98% surround synapses and have effects on synapse dynamics [24]
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