International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Oral Presentation

Monday 18 November

17:00 - 17:15 HRS


M Bucan
University of Pennsylvania

Co-Authors: 1, 2) David Kapfhamer, 1,2) Gillian Leach, 1,2) Yi Sun, 3) Sigrid C. Veasey, 4) John Schimentiand 1, 2, 3) Maja Bucan
Institutions: 1) Department of Genetics, 2) Center for Neurobiology and Behavior in the Department of Psychiatry, 3) Center for Sleep and Respiratory Neurobiology, University of Pennsylvania; 4) The Jackson Laboratory.

The limited availability of appropriate animal models has hindered research in complex neuropsychiatric illnesses. Our approach toward identification of these models involves a) the identification of behavioral traits that can be modeled in rodents; b) identification of mouse mutants with anomalies in these simple behavioral traits; c) the isolation of genes that underlie these traits and the investigation of their relevance to the same or similar traits in humans. Two mutagenesis screens (a genome-wide recessive screen and a Chr 5 region specific screen) currently being undertaken in the lab involve analysis of progeny of chemically (ENU) mutagenized mice using a set of assays: zero maze (anxiety), rotarod (neuromuscular function), analysis of the acoustic startle response (sensory motor gating), wheel running activity and EEG/EMG scoring of sleep patterns (circadian behavior and sleep patterns). This screen identified over 10 rest:activity mutants. We showed that a semidominant mutation, Earlybird, that shortens the circadian period of locomotor is caused by a point mutation in the conserved amino acid (D77G) within the GTP-binding domain of Rab3a, resulting in significantly reduced levels of RAB3A protein. RAB3A is the most abundant RAB (ras-associated binding) protein in the brain and plays a regulatory role in synaptic vesicle trafficking. Phenotypic assessment of Earlybird mice and the previously described null allele of Rab3a revealed anomalies in circadian period and sleep homeostasis, providing evidence for the involvement of RAB3A-mediated synaptic transmission in these behaviors.

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