Figure 4. The tripartite glutamate synapse.

Neuronal glutamate (Glu) is synthesized de novo from glucose (not shown) and from glutamine (Gln) supplied by glial cells. Glutamate is then packaged into synaptic vesicles by vesicular glutamate transporters (vGluTs). SNARE complex proteins mediate the interaction and fusion of vesicles with the presynaptic membrane. Metabotropic glutamate receptors of class II, such as mGlu2 and mGlu3, regulate neuronal release of glutamate into the synaptic space. After release into the synaptic space, glutamate binds to ionotropic glutamate receptors (NMDA receptors (NMDARs) and AMPA receptors (AMPARs)) and metabotropic glutamate receptors (mGluR1 to mGluR8) on the membranes of both postsynaptic and presynaptic neurons and glial cells. Upon binding, the receptors initiate various responses, including membrane depolarization, activation of intracellular messenger cascades, modulation of local protein synthesis and, eventually, gene expression (not shown). Surface expression and function of NMDARs and AMPARs is dynamically regulated by protein synthesis and degradation and receptor trafficking between the postsynaptic membrane and endosomes. The insertion and removal of postsynaptic receptors provide a mechanism for long-term modulation of synaptic strength. Glutamate is cleared from the synapse through excitatory amino acid transporters (EAATs) on neighboring glial cells (EAAT1 and EAAT2) and, to a lesser extent, on neurons (EAAT3 and EAAT4). Within the glial cell, glutamate is converted to glutamine by glutamine synthetase and the glutamine is subsequently released by System N transporters and taken up by neurons through System A sodium-coupled amino acid transporters to complete the glutamate–glutamine cycle. Reprinted from²⁹ by permission.