Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse

被引:64
作者
Kapfhamer, D
Valladares, O
Sun, Y
Nolan, PM
Rux, JJ
Arnold, SE
Veasey, SC
Bucan, M [1 ]
机构
[1] Univ Penn, Ctr Neurobiol Behav, Dept Psychiat, Philadelphia, PA 19104 USA
[2] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Ctr Sleep & Resp Neurobiol, Philadelphia, PA 19104 USA
[4] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA
[5] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1038/ng991
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Rab3a is the most abundant Rab (ras-associated binding) protein in the brain and has a regulatory role in synaptic vesicle trafficking(1). Mice with a targeted loss-of-function mutation in Rab3a have defects in Ca2+-dependent synaptic transmission: the number of vesicles released in response to an action potential is greater than in wildtype mice, resulting in greater synaptic depression(2,3) and the abolishment of CA3 mossy-fiber long term potentiation(4). The effect of these changes on behavior is unknown. In a screen for mouse mutants with abnormal rest-activity and sleep patterns, we identified a semidominant mutation, called earlybird, that shortens the circadian period of locomotor activity. Sequence analysis of Rab3a identified a point mutation in the conserved amino acid (Asp77Gly) within the GTP-binding domain of this protein in earlybird mutants, resulting in significantly reduced levels of Rab3a protein. Phenotypic assessment of earlybird mice and a null allele of Rab3a revealed anomalies in circadian period and sleep homeostasis, providing evidence that Rab3a-mediated synaptic transmission is involved in these behaviors.
引用
收藏
页码:290 / 295
页数:6
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