CLEFT-PALATE AND DECREASED BRAIN GAMMA-AMINOBUTYRIC-ACID IN MICE LACKING THE 67-KDA ISOFORM OF GLUTAMIC-ACID DECARBOXYLASE

In addition to its role as an inhibitory neurotransmitter, gamma-amino butyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system, GABA is synthesized by glutamic arid decarboxylase (GAD), but the respective roles of its two isoforms (GA D65 and 67) have not been determined, The selective elimination of eac h GAD isoform by gene targeting is expected to clarify these issues, R ecently we have produced GAD65 -/- mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except f or a slight increase in susceptibility to seizures, Here we report the production of GAD67 -/- mice, These mite were born at the expected fr equency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, r espectively, in the cerebral cortex of the newborn GAD67 -/- mice. The ir brain, however, did not show any discernible defects, Previous phar macological and genetic investigations have suggested the involvement of GABA in palate formation, but this is the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.