A MusD retrotransposon insertion in the mouse Slc6a5 gene causes alterations in neuromuscular junction maturation and behavioral phenotypes.
A MusD retrotransposon insertion in the mouse Slc6a5 gene causes alterations in neuromuscular junction maturation and behavioral phenotypes.
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DOI：
10.1371/journal.pone.0030217
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Burgess RW
中科院分区：
文献类型：
--
作者：
Bogdanik LP;Chapman HD;Miers KE;Serreze DV;Burgess RW
甘氨酸是脊髓和某些脑区的主要抑制性神经递质。突触前甘氨酸转运蛋白GlyT2是通过突触前甘氨酸再摄取和再循环进行持续甘氨酸能传递所必需的。编码GlyT2的SLC6A5的突变在人类中引起遗传性的过度兴奋，在敲除小鼠中引起类似的表型，并且变体与精神分裂症相关。我们确定了小鼠Slc6a5中的自发突变，由MusD逆转录转座子插入引起。GlyT2蛋白在纯合突变体中检测不到，表明无效等位基因。纯合子突变小鼠在出生时是正常的，但在五天大时出现处理诱导的痉挛，并且只能存活两周，但允许研究早期活动调节的发育过程。在神经肌肉接头处，突触消除和从胚胎到成人乙酰胆碱受体亚基的转换加速，与运动神经元活性的推测增加一致，并且乙酰胆碱受体的转录升高。杂合子小鼠的寿命没有减少，但GlyT2水平降低，热板试验显示其热敏感性正常，但在重复梳理和家庭笼监测睡眠时间减少方面存在差异。旷场和高架十字迷宫测试没有检测到焦虑样行为，然而，后者表现出多动表型。重要的是，在小鼠精神分裂症模型中观察到理毛和活动过度。因此，突变Slc6a5显示神经肌肉接头发育的变化作为纯合子，和行为表型作为杂合子，表明其有用的甘氨酸能功能障碍相关的研究。
Glycine is the major inhibitory neurotransmitter in the spinal cord and some brain regions. The presynaptic glycine transporter, GlyT2, is required for sustained glycinergic transmission through presynaptic reuptake and recycling of glycine. Mutations in SLC6A5, encoding GlyT2, cause hereditary hyperekplexia in humans, and similar phenotypes in knock-out mice, and variants are associated with schizophrenia. We identified a spontaneous mutation in mouse Slc6a5, caused by a MusD retrotransposon insertion. The GlyT2 protein is undetectable in homozygous mutants, indicating a null allele. Homozygous mutant mice are normal at birth, but develop handling-induced spasms at five days of age, and only survive for two weeks, but allow the study of early activity-regulated developmental processes. At the neuromuscular junction, synapse elimination and the switch from embryonic to adult acetylcholine receptor subunits are hastened, consistent with a presumed increase in motor neuron activity, and transcription of acetylcholine receptors is elevated. Heterozygous mice, which show no reduction in lifespan but nonetheless have reduced levels of GlyT2, have a normal thermal sensitivity with the hot-plate test, but differences in repetitive grooming and decreased sleep time with home-cage monitoring. Open-field and elevated plus-maze tests did not detect anxiety-like behaviors; however, the latter showed a hyperactivity phenotype. Importantly, grooming and hyperactivity are observed in mouse schizophrenia models. Thus, mutations in Slc6a5 show changes in neuromuscular junction development as homozygotes, and behavioral phenotypes as heterozygotes, indicating their usefulness for studies related to glycinergic dysfunction.
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影响因子：
11
作者：
Basu, A. C.;Tsai, G. E.;Coyle, J. T.
通讯作者：
Coyle, J. T.
影响因子：
5.7
作者：
Haranishi, Yasunori;Hara, Koji;Sata, Takeyoshi
通讯作者：
Sata, Takeyoshi
影响因子：
5.5
作者：
ECCLES, JC;FATT, P;KOKETSU, K
通讯作者：
KOKETSU, K
影响因子：
5.5
作者：
Alvarez, FJ;Dewey, DE;Fyffe, REW
通讯作者：
Fyffe, REW
影响因子：
5.5
作者：
Bradaïa, A;Schlichter, R;Trouslard, J
通讯作者：
Trouslard, J