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Background  Previous studies have shown that disruption of GABA signaling in mice via mutations in the  Gad1 ,  Gabrb3  or  Viaat  genes leads to the development of non-neural developmental defects such as cleft palate. Studies of the  Gabrb3  and  Gad1  mutant mice have suggested that GABA function could be required either in the central nervous system or in the palate itself for normal palatogenesis.    Methodology/Principal Findings  To further examine the role of GABA signaling in palatogenesis we used three independent experimental approaches to test whether  Gad1  or  Viaat  function is required in the fetal CNS for normal palate development. We used oral explant cultures to demonstrate that the  Gad1  and  Viaat  mutant palates were able to undergo palatogenesis in culture, suggesting that there is no defect in the palate tissue itself in these mice. In a second series of experiments we found that the GABA A  receptor agonist muscimol could rescue the cleft palate phenotype in  Gad1  and  Viaat  mutant embryos. This suggested that normal multimeric GABA A  receptors in the CNS were necessary for normal palatogenesis. In addition, we showed that CNS-specific inactivation of  Gad1  was sufficient to disrupt palate development.    Conclusions/Significance  Our results are consistent with a role for  Gad1  and  Viaat  in the central nervous system for normal development of the palate. We suggest that the alterations in GABA signaling lead to non-neural defects such as cleft palate as a secondary effect due to alterations in or elimination of fetal movements.

Cleft Palate Is Caused by CNS Dysfunction in Gad1 and Viaat Knockout Mice