Pathophysiology associated with a single gene (MASS1) mutation underlying the robust audiogenic seizure phenotype in Frings mice

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Title Pathophysiology associated with a single gene (MASS1) mutation underlying the robust audiogenic seizure phenotype in Frings mice
Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Klein, Brian Donald
Date 2003-05
Description The audiogenic seizure (AGS)-susceptible Frings mouse is a genetic model for generalized reflex epilepsy. The single genetic locus responsible for the AGS phenotype in Frings mice, named monogenic audiogenic seizure-susceptible MASS1, has recently been identified but the function of MASS1 is unknown. One goal of the present investigation was to identify the pathophysiology from the Frings MASS1 mutation that leads to the development of the robust AGS-susceptible phenotype. We hypothesized that the Frings MASS1 mutation produces cochlear dysfunction leading to hyperexcitability in the inferior colliculus, and that the MASS1 mutation may exert direct effects on intrinsic neuroexcitability in the brain. The hypothesis was investigated through studies that mapped the AGS network in Frings mice, measured auditory function, examined tonotopic response domains in the inferior colliculus and measured electroconvulsive seizure thresholds (ECT) in mice with and without the MASS1 mutation. Neuronal activation from AGS in Frings mice, as measured by seizure-induced expression of the immediate early gene c-Fos, was limited to a brainstem seizure network. This suggests that an expanded neuronal network is not involved in the robust AGS phenotype. Measuring auditory brainstem responses revealed that the MASS1 mutation produces a moderate and relatively stable early onset hearing impairment. Sound-induced c-Fos expression in the inferior colliculus was used to examine tonotopic neuronal responses to sub-AGS threshold, tone stimulations. The Frings mice displayed significant tonotopic hyper-responsiveness in the inferior colliculus to the subthreshold tone stimulations. This suggests that abnormal neuronal circuits develop in the inferior colliculus as a result of the early onset hearing impairment from the MASS1 mutation. Behavioral ECT testing was used to measure regional neuroexcitability (brainstem, forebrain and limbic structures) associated with the MASS1 mutation. The ECT tests demonstrated that the MASS1 mutation significantly lowered the electroconvulsive threshold in the brainstem and lowered resistance to seizure spread. The studies in this dissertation revealed that the Frings MASS1 mutation produces a moderate and stable hearing impairment that results in a neuronal hyper-responsiveness in the inferior colliculus. These auditory defects, combined with a significantly lowered threshold for brainstem seizures, produce the particularly robust AGS phenotype in the Frings mice.
Type Text
Publisher University of Utah
Subject Genetics
Subject MESH Epilepsy; Mice; Seizures
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Pathophysiology associated with a single gene (MASS1) mutation underlying the robust audiogenic seizure phenotype in Frings mice". Spencer S. Eccles Health Sciences Library. Print version of "Pathophysiology associated with a single gene (MASS1) mutation underlying the robust audiogenic seizure phenotype in Frings mice," available at J. Willard Marriott Library Special Collection. RC39.5 2003 .K58.
Rights Management © Brian Donald Klein.
Format application/pdf
Format Medium application/pdf
Format Extent 2,273,765 bytes
Identifier undthes,4536
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Funding/Fellowship NIH Grant NS38616-01, NIH Contract N01NS42311 NINDS, and the American Doceity for Pharmaceutical Education.
Master File Extent 2,273,790 bytes
ARK ark:/87278/s6445p8w
Setname ir_etd
ID 191349
Reference URL https://collections.lib.utah.edu/ark:/87278/s6445p8w
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