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-aminobutyric acid (GABA) is presumed to be involved in the development and plasticity of the nervous system, GABA is synthesized by glutamic and decarboxylase (GAD), but the respective roles of its two isoforms (GAD65 and 67) have not been determined, The selective elimination of each GAD isoform by gene targeting is expected to clarify these issues, Recently we have produced GAD65-/- mice and demonstrated that lack of GAD65 does not change brain GABA contents or animal behavior, except for a slight increase in susceptibility to seizures, Here we report the production of GAD67 -/-mice, These mite were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn GAD67-/-mice. Their brain, however, did not show any discernible defects, Previous pharmacological 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.