Molecular signals of plasticity at the tetrapartite synapse

Abstract

The emergence of astroglia as an important participant of the synaptic machinery has led to the 'tripartite synapse' hypothesis. Recent findings suggest that synaptic signaling also involves the surrounding extracellular matrix (ECM). The ECM can incorporate and store molecular traces of both neuronal and glial activities. It can also modulate function of local receptors or ion channels and send diffuse molecular signals using products of its use-dependent proteolytic cleavage. Recent experimental findings implicate the ECM in mechanisms of synaptic plasticity and glial remodeling, thus lending support to the 'tetrapartite synapse' concept. This inclusive view might help to understand better the mechanisms underlying signal integration and novel forms of long-term homeostatic regulation in the brain.

Figure 1

The tetrapartite synapse and 12 possible signaling pathways among its four parts. Examples of signaling molecules are given in parentheses. Abbreviations: ATP, adenosine triphosphate; ECM, extracellular matrix; CSPGs, chondroitin sulfate proteoglycans; TNFα, tumor-necrosis factor α.

Figure 2

Mechanisms of plasticity at the tetrapartite synapse: where the ECM and glia get involved. (a) Co-activation of presynaptic and postsynaptic cells results in release and activation of neurotrypsin. The product of agrin cleavage by neurotrypsin, agrin-22, induces formation of dendritic filopodia. (b) Release of d-serine from astroglia and positive modulation of NMDA receptors and l-type Ca²⁺ channels by ECM molecules reelin, tenascin-C and hyaluronan supports induction of LTP. Activation of postsynaptic l-type Ca²⁺ channels may lead to retrograde signaling and an increase in efficacy of presynaptic release. (c) Astroglia-derived ATP is converted into adenosine which, by acting via A1 receptors, can destabilize new synaptic configurations during a consolidation phase of LTP (first 30 min after induction of LTP). Integrin signaling in contrast promotes stabilization of new synaptic configurations promoting polymerization of actin. (d) Presynaptic inactivity leads to release of TNFα from astrocytes that upregulates expression of β3 integrins, which signal to inhibit endocytosis of AMPA receptors, and thus increases their cell surface expression at synapses. Abbreviations: ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CSPGs, chondroitin sulfate proteoglycans; ECM, extracellular matrix; LTP, long-term potentiation; TNFα, tumor-necrosis factorα; TTX, tetrodotoxin, a blocker of voltage-gated Na⁺ channels; X?, unknown factor(s); ↑, stimulation; inhibition; – indirect evidence.