Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse.
Rab3a is the most abundant Rab (ras-associated binding) protein in the brain and has a regulatory role in synaptic vesicle trafficking. Mice with a targeted loss-of-function mutation in Rab3a have defects in Ca(2+)-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 and the abolishment of CA3 mossy-fiber long term potentiation. 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.
Kapfhamer
David
D
Center for Neurobiology of Behavior of the Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Valladares
Otto
O
Sun
Yi
Y
Nolan
Patrick M
PM
Rux
John J
JJ
Arnold
Steven E
SE
Veasey
Sigrid C
SC
Bućan
Maja
M
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D002940:Circadian Rhythm / Q000235:genetics*; D005038:Ethylnitrosourea; D005260:Female; D006706:Homeostasis; D008124:Locomotion / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D017354:Point Mutation; D012892:Sleep Deprivation / Q000503:physiopathology*; D012893:Sleep Wake Disorders / Q000235:genetics; D020826:rab3A GTP-Binding Protein / Q000235:genetics* / Q000502:physiology
D020826:rab3A GTP-Binding Protein; D005038:Ethylnitrosourea