Mutations in RAB3A alter circadian period and homeostatic response to sleep loss in the mouse / David Kapfhamer.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Kapfhamer, David.

Contributor:

Bucan, Maja, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Cell and Molecular Biology.

Academic Dissertations as Topic.

Medical Subjects:

Cell and Molecular Biology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

xi, 257 pages : illustrations ; 29 cm

Production:

2002.

Summary:

The analysis of mutations with behavioral phenotypes in the mouse provides a powerful tool for the study of the genetic basis of complex behaviors. A paucity of existing mouse mutations with behavioral phenotypes prompted us to search for novel rest-activity mutations using a forward genetic approach. Analysis of circadian period in over 500 progeny of mice treated with ENU identified the Earlybird (Ebd) mutation. Candidate gene cloning of Ebd identified a point mutation in a conserved amino acid (D77->G) within the GTP-binding domain of RAB3A, a protein involved in synaptic vesicle trafficking (Geppert et al., 1994; Geppert et al., 1997; Castillo et al., 1997). Complementation analysis of Ebd with a previously described Rab3a knockout line (Geppert et al., 1994) provided evidence that Ebd may be a dominant-negative allele of Rab3a. Phenotypic analysis of Ebd and Rab3a-/- mice demonstrated a shortened period of the activity rhythm, increased intrastrain variance in circadian period, blunted homeostatic response to sleep loss, and reduced prepulse inhibition of acoustic startle in both alleles. In addition, baseline NREM sleep amount is increased and contextual fear conditioning reduced in Rab3a-/- mice. These observations provide evidence for a role of RAB3A-mediated synaptic transmission in the expression of these complex behaviors.

Notes:

Supervisor: Maja Bucan.

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2002.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3073018.

OCLC:

244972861