The biosynthesis of GABA largely depends on the enzyme glutamate decarboxylase (GAD) (Petroff, 2002). Two isoforms of GAD have been identified, GAD1 and GAD2, which previously were called GAD67 and GAD65, respectively. These enzymes couple with pyridoxal phosphate as a cofactor and are responsible for catalyzing glutamate to produce GABA in the brain. In humans, GAD1 maps to chromosome 2q31 and spans about 45 kb, and GAD2 maps to chromosome 10p11.23 with a size about 88 kb. GAD1 and GAD2 are highly similar in their catalytic domains, regional expression, and subcellular localization (Erlander et al., 1991; Feldblum et al., 1995), but are associated with different modes of GABA release. GAD1 is involved in cytosolic GABA synthesis and is responsible for maintaining basal GABA levels, whereas GAD2 is predominately involved in synaptosomal GABA release, and can be rapidly activated when there is high demand for GABA (Soghomonian and Martin, 1998). Rodent studies suggest that GAD1 is important in maintaining GABA levels in the brain, and that the GAD1 knockout is usually lethal. In contrast, GAD2 knockout mice maintain normal brain GABA
