Abstract
Rab3a 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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Acknowledgements
We thank G. Pickard for his contribution in the early stages of this project; A. Dixon-White for technical assistance; R. Buono, A. deBrunier, J. Eberwine and K. Miyashiro for assistance with immunohistochemistry, western analysis and in situ analysis; L. Maltais for assistance with gene nomenclature; and S. Poethig, M. Chou, T. Abel and G. Leach for comments on the manuscript. This work was supported by grants from the US National Institutes of Health.
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Kapfhamer, D., Valladares, O., Sun, Y. et al. Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse. Nat Genet 32, 290–295 (2002). https://doi.org/10.1038/ng991
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DOI: https://doi.org/10.1038/ng991
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