Roles of GABA in the neural structure and function investigated in GAD-deficient mice.

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γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system and synthesized by two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. We produced GAD-deficient mice by homologous recombination and analyzed their brain for further elucidation of the roles of GABA.Brain GABA contents were reduced to 7% in the fetal and newborn GAD67-deficient mice and to 50-70% in the adult GAD65-deficient mice, indicating the importance of GAD67 at the fetal stage and GAD65 at postnatal maturation. Deletion of both isoforms did not induce any serious defects in brain structure. This finding does not support a current hypothesis that GABA is crucial for the neural histogenesis. GAD67-deficient mice showed cleft palate and abnormal activity of respiratory neural network. Adult GAD65-deficient mice showed the abnormality in every emotional behavior test, suggesting higher anxiety and abnormal fear response. Patch-clamp recording of synaptic activities in slice preparation revealed that spontaneous inhibitory transmission was reduced while the excitatory transmission was enhanced in the GAD65-deficient amygdala.