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Date of Award

9-2010

Document Type

Campus Access

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

First Advisor

Gerald B. Downes

Second Advisor

Richard E. van Emmerik

Third Advisor

Abigail M. Jensen

Subject Categories

Cell Biology | Molecular Biology | Neuroscience and Neurobiology

Abstract

Neural networks in the hindbrain and spinal cord require a proper balance between excitation and inhibition. Identification of zebrafish mutants that have defects in motor output mediated by these networks can allow entrée into underlying network mechanisms. techno trouser ( tnt ) mutants demonstrate abnormal motor behavior. Two days after fertilization, wild-type larvae perform an escape response consisting of a large-amplitude body bend away from touch stimuli followed by smaller amplitude body bends to swim away. tntmutants perform an initial large amplitude body bend away from touch stimuli, but the following smaller amplitude body bends are interrupted by several, abnormal, large amplitude body bends. Four days after fertilization, wild-type larvae exhibit faster escape behavior, whereas tnt mutants are nearly paralyzed and shorter along the rostral-caudal axis. We used meiotic mapping and candidate gene analysis to reveal that thetnt mutation disrupts slc1a2b , which encodes EAAT2, a glutamate transporter expressed in glial cells. Lesion analysis, in situ hybridization, and in vivo electrophysiological recordings all support a model in which reducedslc1a2b function results in exuberant excitation of neurons, initially in the hindbrain and later in development in the spinal cord, to produce the large-amplitude body bends and subsequent paralysis of tnt mutants. Since disruption of human EAAT2 is thought to promote several different neurological diseases, including epilepsy and amyotrophic lateral sclerosis, tnt mutants provide a new tool to understand these disorders.

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