Gastrointestinal phenotype of GAD67lacZ transgenic mice with early postnatal lethality

It has been proposed that gamma-aminobutyric acid (GABA) in the gut may function as a neurotransmitter, hormone and/or paracrine agent. Our aim was to examine transgenic mice of the GAD67-lacZ line with impaired postnatal growth and early postnatal lethality for gastrointestinal abnormalities. The gastrointestinal tract was dissected and processed for histology, immunohistochemistry, electron microscopy, western blotting and measurement of GAD activity. Homozygous mice of both sexes displayed an intestinal phenotype characterized by a fragile and haemorrhagic intestinal wall, a reduced number of villi, epithelial lesions and the occasional appearance of pseudostratified epithelium. The number of GABA-immunoreactive enteroendocrine cells and mucin-secreting goblet cells increased significantly relative to wild-type epithelium. The appearance of GABA-immunopositive neuronal perikarya and the lack of GABA-immunoreactive varicose fibres were observed in the enteric plexuses of transgenic mice. Tissue homogenates of transgenic mice showed higher levels of expression of GAD67 and GAD65 as compared with wild-type mice. Our results suggest that the possible reason underlying the growth impairment and postnatal lethality observed in GAD67 transgenic mice is a functional impairment of GABAergic enteric neurons and disintegration of intestinal epithelium.