Roles of GABA in the development of the nervous system : analysis of GAD-deficient mice

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γ-Aminobutyric acid (GABA) is synthesized from glutamate by two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In order to further elucidate the roles of GABA in the developing and mature brain, we have generated GAD gene-knockout mice and analyzed their phenotypes. While GAD65 is developed postnatally and its deficiency results in seizure and abnormal emotional behavior, expression of GAD67 starts simultaneously with differentiation of GABAergic neuron at an early embryonic stage. Development of GABAergic neurons was studied in the superior colliculus (SC) of the GAD67+/- and GFP+/- mice. Although the SC is layered structure as the neocortex, its GABAergic neurons were originated together with other neurons from the nearby ventricular zone. Before GABAergic neurons were differentiated in the SC, abundant GABAergic fibers were transiently present on the surface. They originated probably outside of SC and crossed the midline, suggesting their developmental roles. GAD67-/- mice contained less than 10% of GABA compared with the wild type but did not show any serious defect in their brain structure. Neural function of GAD67 knockout mice did not survive after birth because of cleft plate and their neural function could not studied in adult animals. When the brainstem isolated from the embryo or newborn was studied electrophyiologically, respiratory rhythm and inhibitory synaptic currents in respiratory neurons were greatly impaired.