The dual role of the extracellular matrix in synaptic plasticity and homeostasis

Key Points Several extracellular matrix (ECM) components, such as Reelin, integrin ligands, tenascin C and hyaluronic acid, regulate induction of synaptic plasticity through their modulatory effects on NMDA ( N -methyl- D -aspartate) receptors and L-type voltage-dependent Ca 2+ channels, which are the major players in triggering activity-dependent synaptic changes. Following induction of long-term potentiation (LTP), stabilization of new synaptic configurations requires integrin signalling through the Src family of tyrosine kinases, which contributes to the regulation of the localization and activity of small GTPases that coordinate actin cytoskeleton remodelling and stabilization. β3 integrins and neuronal pentraxins regulate homeostatic scaling of excitatory postsynaptic currents on excitatory and inhibitory neurons, respectively, through control of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor trafficking and aggregation. Tenascin R is important for metaplastic adjustment of the threshold for induction of LTP in area CA1 of the hippocampus, where it regulates perisomatic innervation of pyramidal neurons. Stabilization of functional microcircuits at the end of the 'critical period' in brain development is thought to involve formation of the chondroitin sulphate-rich ECM that serves as an inhibitory 'barrier' to restrain structural plasticity in the visual cortex and enable formation of erasure-resistant emotional memories in the amygdala. Activity-dependent proteolytic cleavage of ECM components regulates various forms of synaptic plasticity. Proteolytic activity of matrix metalloproteinase 9 promotes hippocampal LTP through the activation of integrin-dependent signalling. Integrin activation is mediated by proteolytic unmasking of a cryptic Arg-Gly-Asp motif of a not yet identified ECM component. The proteolytic function of the synaptic serine protease neurotrypsin is activated in an NMDA receptor-dependent manner when a presynaptic and a postsynaptic neuron fire together. Cleavage of agrin by neurotrypsin unmasks a previously unaccessible filopodia-promoting site on the released carboxy-terminal 22-kDa fragment (agrin 22). Activity-dependent generation of dendritic filopodia by released agrin 22 is thought to contribute to activity-dependent synaptogenesis and reorganization of neural circuits. The extracellular matrix (ECM) plays a key part in diverse cellular processes. Dityatev and colleagues review how the ECM can have oppos