Sex-Specific Brian Auditory and Motor Tract Neurodegeneration and Seizure Development in Mice with a Deficiency in Micronutrient Selenium Metabolism.

Kremer, Penny M.

Sex-Specific Brian Auditory and Motor Tract Neurodegeneration and Seizure Development in Mice with a Deficiency in Micronutrient Selenium Metabolism.

Files

2017-08-phd-kremer.pdf (2.28 MB)

Date

2017-08

Authors

Kremer, Penny M.

Department

Cell & Molecular Biology

Abstract

Selenium (Se) is an essential micronutrient element linked to many biological functions in human health (1). Two proteins involved in Se metabolism are Selenoprotein P (Sepp1) and Selenocysteine lyase (Scly). Previous studies in our lab showed that when both Sepp1 and Scly were disrupted, male double knockout Se-supplemented mice (MDKOSe) exhibited decreased survival, severe neurological impairment and susceptibility to audiogenic seizures (AGS) (2). Further investigation indicates that between 70 and 80% of MDKOSe mice will develop seizure characteristics between 8 and 12 weeks of age, with about 40% requiring euthanasia prior to 10 weeks. A significant decrease in motor coordination starting around 6 weeks of age along with wobbly or abnormal gait precedes seizure development. Seizures occur within a week of weight loss commencement, accompanied by a decrease in food and water intake. Female DKOSe mice have decreased motor coordination starting at 7 weeks of age and increased percentage of inguinal and gonadal white adipose tissue fat deposits and elevated serum glutathione peroxidase 3 levels. The neurological deficit becomes severe, leading to seizure development if high selenium supplementation is removed at weaning. Disruption of the maturation of GABAergic inhibition seems to be the main neurological effect leading to the development of AGS in MDKOSe mice. Preadolescent castration rescues the MDKOSe phenotype. It delays onset of neuromotor deficits in male Sepp1 knockout mice on a Se deficient diet and is protective of male wild type mice exposed to the neurotoxin dizocilpine maleate (MK-801). Testosterone re-administration to sham-operated MDKOSe mice appears to be beneficial but not preventative. Together, these results indicate that there is a critical time point in which Se is essential for the prevention of neurological impairment in both female and male DKOSe mice. MDKOSe may have a greater need for Se during the course of their sexual reproductive period due to competition between the testes and the brain for Se. The specific deficits in behavioral tests and underlying GABAergic system maturation disruption could allow DKOSe mice to potentially serve as a model for the study of ictogenesis and therapeutic drug testing of novel drugs for epileptic patients.

Keywords

Neurodegeneration, Micronutrient, Selenium, Sex Specific, Seizure Development

URI

http://hdl.handle.net/10125/62236

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Ph.D. - Cell and Molecular Biology

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