演題番号 : P1-a33
柿崎 利和 / Toshikazu Kakizaki:1 斉藤 憲史 / Kenzi Saito:1 加家壁 美樹子 / Mikiko Kayakabe:1 柳川 右千夫 / Yuchio Yanagawa:1
1:群馬大院・医・遺伝発達行動 / Dept Genetic and Behavioral Neurosci, Univ of Gunma, Maebashi
Glutamate decarboxylase (GAD) biosynthesizes neurotransmitter GABA, and vesicular GABA transporter (VGAT) transports GABA and another neurotransmitter glycine into synaptic vesicle. Several knockouts (KOs) of genes, including GAD67 or VGAT, relating to GABAergic neurotransmission lead to developmental failure, cleft palate and omphalocele. And, palate explants from GAD67 or VGAT KO fetuses developed normally, and CNS-specific GAD67 KO fetuses displayed cleft palate and omphalocele, indicating that GABAergic signaling in CNS plays significant roles in prenatal stages in vivo. On the other hand, the presence of glycinergic signaling has been suggested by electrophysiological and histological studies in developing CNS. Prenatal in vivo function of glycinergic neurotransmission, however, remains unclear. We found that GAD65/GAD67 double KO (GADs DKO) mice displayed cleft palate, and the phenotypes of GADs DKO fetuses were less severe than those of VGAT KO fetuses. These results suggest that not only GABAergic but also glycinergic neurotransmissions are involved in palatogenesis and body wall formation. To strengthen the possibility that glycinergic neurotransmission plays a significant role in palatogenesis, we planned to examine the effect of an enhanced glycinergic neurotransmission on the formation of palate in VGAT KO and GADs DKO fetuses. We injected the GlyT1 inhibitor NFPS, that inhibits the clearance of glycine in synaptic cleft, into lateral ventricles of VGAT KO and their littermate control fetuses in utero. All NFPS-injected VGAT KO fetuses displayed cleft palate (n=3). And 29% (n=7) and 50% (n=8) of wild-type and heterozygous VGAT KO littermate fetuses also displayed cleft palate. On the other hand, vehicle injection caused cleft palates in 0% (n=4) and 25% (n=4) of wild-type and heterozygous VGAT KO fetuses, respectively. These results suggest that GlyT1 inhibitor caused cleft palate rather than suppressed the occurrence of cleft palate.