Molecular signals of plasticity at the tetrapartite synapse

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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.

Introduction

Chemical synapses are elemental units of information processing in the brain. By implication, signal transfer between presynaptic and postsynaptic cells has been considered as a bipartite mechanism. Over the last decade, however, the emergence of astrocytes as an important local player has led to the concept of the tripartite synapse [1]. Recent findings suggest that all parts of the tripartite synapse interact, either directly or through soluble signaling molecules, with the extracellular matrix (ECM) [2, 3, 4, 5]. ECM structures are formed in an activity-dependent manner and incorporate molecular signatures of both glial and synaptic elements. In turn, ECM molecules modulate activities of pre- and postsynaptic receptors and ion channels. The ECM can respond to network activity either by incorporating secreted molecules and shed extracellular domains of transmembrane molecules, or by freeing products of its activity-dependent proteolytic cleavage as signaling messengers [6]. These observations have suggested that the ECM is a fourth essential element of what could be termed as the ‘synaptic quadriga’ [7] or the ‘tetrapartite synapse’ [8]. Theoretically, including the ECM as a fourth player increases the number of interaction pathways in a synapse from 6 to 12 (Figure 1). Here we briefly review the underlying mechanisms, focusing on interactions beyond the classical pre–postsynaptic exchange, namely on signals between neurons, astroglia and the ECM.

Section snippets

Presynaptic signals to glia and ECM

The bulk of information in the brain is processed via excitatory glutamatergic synapses. Once released, glutamate activates receptors inside the synaptic cleft but it can also reach some high-affinity receptors outside the cleft [9, 10, 11]. The excess of glutamate is rapidly buffered by high-affinity transporters [12, 13, 14] expressed in abundance by the surrounding astroglia [15, 16]. Glial transporters EAAT1–EAAT2 account for >90% of brain glutamate uptake [17], and astrocytic protrusions

Postsynaptic signals to glia and ECM

Quantitative electron microscopy suggests that astroglia occur more frequently on the postsynaptic side of some excitatory synapses [21]. Several types of retrograde messengers are released from postsynaptic neurons, including neurotransmitters, endocannabinoids, gasses, and peptides, as detailed in a recent review [40]. Similar to axonal releases, ectopic release of glutamate and GABA from postsynaptic dendrites could exert receptor actions in astrocytes (see above), but little is known about

Astroglial signals

Ca2+ signals in astrocytes could trigger release of glutamate [32, 44, 50], ATP [33, 34, 51], D-serine [52, 53, 54•], the pro-inflammatory cytokine tumor-necrosis factor α (TNFα), and other signaling molecules. Whether and how the underlying mechanisms differ, in terms of their Ca2+-dependent molecular machinery and subcellular localization, remains intensely debated [29]. Presynaptic NMDARs and metabotropic glutamate receptors could be a target of glutamate released from astrocytes [44, 45•]

ECM signals

All members of the thrombospondin gene family trigger the formation of presynaptically active contacts in vitro, and double knockout mice deficient in thrombospondins 1 and 2 show reduced synaptic numbers [66]. This synaptogenic activity is mediated by the α2δ-1 Gabapentin receptor that is part of neuronal voltage-gated calcium channels (VGCCs) [67]. An extracellularly secreted protein, leucine-rich glioma-inactivated 1 (LGI1), has been found to interconnect presynaptic and postsynaptic

Outlook

We are only beginning to appreciate the many forms of functional and structural synaptic changes that rely on interactions with the ECM and the surrounding astroglia. The relationship between perisynaptic ECM and local astrocytic processes remains particularly poorly understood even though it may be essential for the formation and use-dependent modification of synaptic environment. By restraining glial processes and by counteracting the effects of glia-derived adenosine [56], the ECM may

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

A. Dityatev is supported by the Italian Institute of Technology and by a grant from the Government of the Russian Federation. D.A. Rusakov is supported by the Wellcome Trust and Medical Research Council (UK). This work was supported by the COST Action BM1001 ‘Brain Extracellular Matrix in Health and Disease’.

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