Another biologic method for preventing excessive glutamate in the synapse is glutamate’s synthesis from glutamine intracellularly.34 Glutamine can be transported into and out of the synapse without inducing neurotoxicity. The metabolism of glutamate to glutamine occurs primarily in glial cells via the enzyme glutamine synthetase. Glutamine is then transported (glutamine transporter (GlnT), which is common to both glia and neurons and encoded by the Slc38a gene family) out of the glial cell. In turn, glutamine is transported out of the perisynapse and into the excitatory presynaptic compartment. Glutamine is then converted to glutamate by glutaminase and transported to the synaptic membrane, or shunted into GABA synthesis via glutamate decar-boxylase (GAD). Glutamate is also metabolized by glutamate dehydrogenase–yielding alpha-ketoglutarate, which enters the TCA/Krebs cycle.
