Nature Genetics
32, 290 - 295 (2002)
Published online: 16 September 2002; | doi:10.1038/ng991
Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouseDavid Kapfhamer1, Otto Valladares1, Yi Sun1, Patrick M. Nolan1, John J. Rux2, Steven E. Arnold1, Sigrid C. Veasey3, 4
& Maja Bu an1, 3, 51
Center for Neurobiology of Behavior of the Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. 2
The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania, USA. 3
Center for Sleep and Respiratory Neurobiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. 4
Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. 5
Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Correspondence should be addressed to Maja Buan bucan@pobox.upenn.eduRab3a is the most abundant Rab (ras-associated binding) protein in the brain and has a regulatory role in synaptic vesicle trafficking1. 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 depression2,
3 and the abolishment of CA3 mossy-fiber long term potentiation4. 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.
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