Cleft palate by picrotoxin or 3-MP and palatal shelf elevation in GABA-deficient mice.
gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system. Gene targeting of GABA-synthetic glutamic acid decarboxylase (GAD) 67 and GABAA receptor beta(3) subunit induces cleft palate in the mouse. These findings appear to contradict previous pharmacological investigations using benzodiazepines and GABA itself, which indicate that GABA suppresses palatogenesis. Therefore, the effects of picrotoxin and 3-mercaptopropionic acid (3-MP) on palate formation were investigated in the present study. Picrotoxin and 3-MP impair GABA functions by blocking the GABA receptor and synthesis, respectively. Pregnant mice in the critical period [Embryonic Day (E) 11-15] of palatogenesis were administered these substances by subcutaneous injection or continuous infusion at subconvulsive doses, and their fetuses at E17-18 were investigated. A complete cleft in the secondary palate was observed in 15% of 333 embryos in 28 litters. In the remaining fetuses, a complete cleft palate was not observed, but microscopic examination of serial sections revealed partial defects of the palate. Furthermore, rescue from cleft palate in GAD67-deficient mice was attempted by GABA infusion. Horizontal elevation of palatal shelves, which is not observed in nontreated mice, did occur after the infusion in all 14 GABA-infused GAD67-deficient fetuses, although cleft palate still persisted. These results indicate that GABA is required for palatogenesis and is consistent with findings in gene knockout mice.
Ding
Rigao
R
Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki, Japan.
Tsunekawa
Naoko
N
Obata
Kunihiko
K
D015097:3-Mercaptopropionic Acid / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D002972:Cleft Palate / Q000139:chemically induced* / Q000188:drug therapy; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000633:toxicity; D018756:GABA Antagonists / Q000633:toxicity*; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010159:Palate / Q000187:drug effects / Q000196:embryology; D010852:Picrotoxin / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000172:deficiency* / Q000627:therapeutic use
D015097:3-Mercaptopropionic Acid; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D005968:Glutamate Decarboxylase; D007527:Isoenzymes; D010852:Picrotoxin; D005680:gamma-Aminobutyric Acid; C402565:glutamate decarboxylase 1