Thinking outside the cleft to understand synaptic activity: contribution of the cystine-glutamate antiporter (System xc-) to normal and pathological glutamatergic signaling

Abstract

System x(c)(-) represents an intriguing target in attempts to understand the pathological states of the central nervous system. Also called a cystine-glutamate antiporter, system x(c)(-) typically functions by exchanging one molecule of extracellular cystine for one molecule of intracellular glutamate. Nonvesicular glutamate released during cystine-glutamate exchange activates extrasynaptic glutamate receptors in a manner that shapes synaptic activity and plasticity. These findings contribute to the intriguing possibility that extracellular glutamate is regulated by a complex network of release and reuptake mechanisms, many of which are unique to glutamate and rarely depicted in models of excitatory signaling. Because system x(c)(-) is often expressed on non-neuronal cells, the study of cystine-glutamate exchange may advance the emerging viewpoint that glia are active contributors to information processing in the brain. It is noteworthy that system x(c)(-) is at the interface between excitatory signaling and oxidative stress, because the uptake of cystine that results from cystine-glutamate exchange is critical in maintaining the levels of glutathione, a critical antioxidant. As a result of these dual functions, system x(c)(-) has been implicated in a wide array of central nervous system diseases ranging from addiction to neurodegenerative disorders to schizophrenia. In the current review, we briefly discuss the major cellular components that regulate glutamate homeostasis, including glutamate release by system x(c)(-). This is followed by an in-depth discussion of system x(c)(-) as it relates to glutamate release, cystine transport, and glutathione synthesis. Finally, the role of system x(c)(-) is surveyed across a number of psychiatric and neurodegenerative disorders.

Fig. 1.

This schematic depicts an excitatory synapse that is ensheathed by astrocytic processes in an asymmetrical manner, resulting in a greater distance between glial processes and neurons on the presynaptic aspect of the synapse. Glu release in response to synaptic activation quickly reaches a concentration in the synaptic cleft capable of stimulating low-affinity AMPA receptors (A) that are located proximal to the release sites, as well as laterally distributed high-affinity receptors including NMDA (N) and mGlu receptors (M). Diffusion and clearance by excitatory amino acid transporters (E) are thought to rapidly lower the levels of extracellular glutamate in the synaptic cleft. Glutamine (Glt) is released by astrocytes and is considered to be a critical substrate needed to replenish neuronal glutamate stores. In addition to glutamine, astrocytes are also capable of releasing glutamate. The illustration depicts system x_c⁻ (X), which exchanges cystine (C-C) and glutamate on a 1:1 stoichiometry, the direction of the exchange being determined by relative substrate concentration gradients. Glutamate release from system x_c⁻, which is also described as a cystine-glutamate exchanger or antiporter, has been shown to regulate synaptic neurotransmitter release by stimulating extrasynaptic glutamate receptors.

Fig. 2.

This illustration depicts extracellular Glu that is compartmentalized into distinct microdomains. In synapses ensheathed by astrocytes, excitatory amino acid transporters (E) are thought to limit overflow of glutamate and thereby inhibit cross-talk between neighboring synapses (depicted as zone 1 and zone 3) even under periods of high neuronal activity. This provides spatial resolution by restricting the source of glutamate capable of stimulating NMDA (N), AMPA (A), and metabotropic (M) receptors. In addition to the cleft, the extrasynaptic space separating synapses (zone 2) may be a critical site for glutamatergic signaling. Within this space, glutamate transporters, astrocytic glutamate release mechanisms, and functional extrasynaptic receptors are expressed. This supports the intriguing scenario that multiple signaling microdomains may separate neighboring synapses.

Fig. 3.

System x_c⁻ (X)-mediated cystine uptake is a critical determinant of cellular antioxidant capabilities. In astrocytes, cystine (C-C) transported into the cell is reduced into Cys, which can then be used for GSH synthesis by the sequential activity of glutamate cysteine ligase (GCL) and GSH synthetase (GS). GSH can be released by astrocytes via muldrug resistance-asociated protein 1 (MRP-1) transporters, where it is degraded by γ-glutamyl-transpeptidase (γGT) and aminopeptidase N (AP-N). This provides an extracellular source of cysteine that is transported into neurons by the neuronal glutamate transporter EAAT3 (E) to support glutathione production in these cells. In addition, cysteine may also oxidize in the oxygen-rich extracellular space, thereby supplying cystine to support system x_c⁻ activity.

Fig. 4.

This model illustrates cocaine-induced changes in the nucleus accumbens core. Relative to drug-naive counterparts, cocaine-withdrawn rats exhibit reduced glutamate release by system x_c⁻ (X), reduced glutamate clearance by the excitatory amino acid transporter GLT-1 (E)—both of which may contribute to synaptic overflow of Glu after a cocaine injection. As depicted, reduced system x_c⁻ activity results in reduced basal extrasynaptic glutamate, which contributes to diminished mGluR2 (M)-mediated inhibition of synaptic glutamate. In addition, reduced glutamate clearance permits glutamate to spill over into compartments that are more distal. As discussed in the text, the nature of glutamate dysfunction may not be due solely to increased activity of postsynaptic metabotropic, AMPA (A), or NMDA (N) receptors but could be due to altered patterns of activation arising from a loss of signal fidelity that results from “cross talk” of glutamate from distinct microdomains. C-C, cystine.

Fig. 5.

This schematic depicts aspects of cellular organization in the cortex that may be relevant for synchronization of network activity. GABAergic interneurons (I) are thought to contribute to network synchrony, in part because they synapse onto multiple pyramidal cells (P). The cellular architecture also supports a role for astrocytes in network synchronization. As described in section V.A.2, a single astrocyte in the human cortex has a domain that contains an estimated 2 million synapses and is capable of altering the membrane potential of large populations of neurons.