The Influence of GABA Metabolism on GABA Neurotransmission: The Role of Metabolic Regulatory Points and a Neuronal Glutamate Transporter

82 | 2010 | VOLUME 1 VANDERBILT REVIEWS | NEUROSCIENCE ©2010 Vanderbilt Brain Institute. All rights reserved. GLUTAMATE AND GABA METABOLISM Glutamate and GABA are the major excitatory and inhibitory neurotransmitters in the brain, respectively. Unlike other neurotransmitter systems, such as monoamines, reuptake and recycling of glutamate and GABA does not appear to be as important as new synthesis to replenish the pool of neurotransmitter for synaptic vesicle filling. Despite the critical importance of neurotransmitter supply, either to prevent depletion and maintain stable transmission or perhaps to dynamically adjust in response to demand, the metabolic pathways by which these transmitters are continuously supplied to synaptic terminals have not been resolved. GABA is synthesized by the decarboxylation of glutamate, which is catalyzed by the enzyme glutamic acid decarboxylase (GAD). Neurons are not capable of synthesizing glutamate on their own; therefore inhibitory neurons, like excitatory neurons, need a supply of glutamate. At least two possible pathways through which glutamate may be acquired exists: (1) the direct uptake of extracellular glutamate or (2) the uptake of glutamine, which can be converted to glutamate by neurons. Transporters serving both of these roles are expressed by GABAergic neurons, and both have been demonstrated to play roles in the synthesis of GABA. GABA synthesis and synaptic vesicle filling are tightly coupled processes as revealed by biochemical assays. GAD65, the synaptically localized isoform of GAD, is associated with a complex of proteins on synaptic vesicles that includes the vesicular GABA transporter. GABA synthesized from glutamate is taken up into synaptic vesicles preferentially over preexisting GABA. Electrophysiological studies demonstrated that inhibiting GAD results in a reduction in the size of miniature synaptic events, which represent the amount of GABA released from a single synaptic vesicle. In contrast, knock-out of the predominant membrane transporter for GABA reuptake does not influence the size of these miniature events. Taken together, these findings suggest that new synthesis is more important than recycling of existing GABA. Moreover, they demonstrate that any factors influencing GABA synthesis are likely to play an important role in maintaining, and possibly regulating, inhibitory synaptic transmission. Finally, GABA is catabolized by the action of GABA transaminase (GABA-T), which deaminates GABA to make succinic semialdehyde (SSA), and then SSA dehydrogenase (SSADH) converts SSA to succinate, which enters the TCA cycle. SSA can also be converted to γ–hydroxybutyrate (GBH) by the action of SSA reductase (Figure 1).