The extracellular matrix and perineuronal nets in memory

Abstract

All components of the CNS are surrounded by a diffuse extracellular matrix (ECM) containing chondroitin sulphate proteoglycans (CSPGs), heparan sulphate proteoglycans (HSPGs), hyaluronan, various glycoproteins including tenascins and thrombospondin, and many other molecules that are secreted into the ECM and bind to ECM components. In addition, some neurons, particularly inhibitory GABAergic parvalbumin-positive (PV) interneurons, are surrounded by a more condensed cartilage-like ECM called perineuronal nets (PNNs). PNNs surround the soma and proximal dendrites as net-like structures that surround the synapses. Attention has focused on the role of PNNs in the control of plasticity, but it is now clear that PNNs also play an important part in the modulation of memory. In this review we summarize the role of the ECM, particularly the PNNs, in the control of various types of memory and their participation in memory pathology. PNNs are now being considered as a target for the treatment of impaired memory. There are many potential treatment targets in PNNs, mainly through modulation of the sulphation, binding, and production of the various CSPGs that they contain or through digestion of their sulphated glycosaminoglycans.

Fig. 1. The CNS extracellular matrix.

Synapses are tripartite structures involving pre-and postsynaptic structures and astrocytes. All synapses are embedded in interstitial extracellular matrix (iECM), which regulates the extracellular volume, but some synapses are also surrounded by a condensed form of ECM, the PNNs, consisting mainly of CSPGs attached to a hyaluronan backbone.

Fig. 2. Memory effects of chondroitinase digestion.

A Eyeblink conditioning learning is increased by ChABC to the cerebellar nuclei but persistence is decreased. In fear memory PNN digestion enables extinction. B Spontaneous object recognition is assessed in a Y-maze, animals distinguishing between familiar and non-familiar objects in the arms. After 5 min exposure to objects, memory gradually decays and by 24 h is mostly lost. ChABC treatment prolongs memory in young animals, restores it in models of Alzheimer’s and ageing. C The Morris water maze tests place learning: ChABC treatment increases reversal and short-term learning. Grid cells provide a map of the external world: the grid cell map is destabilized by ChABC treatment. D The trial-unique nonmatching-to-location assay (TUNL) is a hippocampus-dependent automated test of location memory. Memory acquisition is enhanced by ChABC treatment. E In normal animals, ChABC digestion impairs social memory, but in animals with defective social memory due to abnormal PNNs, digestion restores memory F ChABC digestion increases the agility of auditory relearning and decreases firing of fast-spiking neurons.

Fig. 3. Effects of external events, neurodegeneration and ageing on the CNS extracellular matrix.

A Stressful early life events, social isolation, social defeat and fear conditioning all have effects on numbers and intensity of PNNs. B Drugs of abuse have various and complex effects on PNN formation in different brain areas: please refer to the text. C During ageing, the sulphation pattern of PNNs changes, with a loss of permissive 6-sulphated CSPGs, leaving a predominance of inhibitory 4-sulphated forms. In addition, hyaluronan chains, which form the backbone of PNNs, become degraded into shorter fragments with unknown effects on memory. D The CNS ECM participates in neurodegenerative conditions. Proteoglycans participate in formation of tau tangles and beta-amyloidβ (Aβ) aggregates. In Huntington’s disease PNNs are engulfed by activated microglia.