Seizures are intermittent yet the underlying stimulus is constantly present, thus, seizure discharge must be set off by some initiating factor.
The aim of this project is to assess the role of thyroid hormones in altering susceptibility of the brain to experimentally- induced seizures and to determine the site and mechanisms involved in this action. The project will study the role of thyroid hormones in brain development and aging from a neurophysiological and neurochemical standpoint. The hypothesis is that thyroid hormones alter seizure susceptibility through changes in cation and anion transport processes in neurons and/or glia by regulating the activities of the transport enzymes, Na+, K+-ATPase, Ca++, Mg++- ATPase, HCO3-ATPase, and carbonic anhydrase. A key role of thyroid hormone appears to be regulation of anion and cation transport via the mitochondrial enzyme, HCO3-ATPase, the cytosolic and membrane- bound enzyme, carbonic anhydrase, and Na+/K+-ATPase during early neuronal and/or glial development. HCO3-ATPase, in particular, appears to trigger the development of these two cell types. In the absence of adequate thyroid hormone during a critical period of maturation, the expressions of HCO3-ATPase as well as carbonic anhydrase and Na+/K+-ATPase activities in neurons and/or glia are delayed with resultant anatomical and biochemical alterations in brain characteristic of the hypothyroid state that cause increased seizure susceptibility. Our observations support this hypothesis. Thus, the activity of HCO3-ATPase exhibits a """"""""spike-like"""""""" increase in activity at 3 and 12 postnatal days, responses that are attenuated by methimazole-induced hypothyroidism. These changes increase susceptibility to seizures. This hypothesis will be tested by biochemical and pharmacological approaches in vivo and in isolated glial and neuronal cell cultures. The activity of transport enzymes, the concentration of electrolytes, and the contents of DNA and protein will be determined in brain of rats and mice with hypothyroid or hyperthyroid states and the results correlated with thyroxine triiodothyronine and thyrotropin levels in plasma, iodothyronine 5'- and 5-monodeiodinase activities in brain and other tissues, and changes in brain excitability during maturation. The studies in mice will use genetic models of epilepsy that exhibit age-dependent alterations in thyroid status (DBA mice) and models of hypothyroidism (hyt/hyt mice). Since hypothyroidism in infants produce cretinism, understanding the processes by which this occurs is of great importance in the clinical control of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021255-08
Application #
3402206
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-09-09
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1994-08-31
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Wang, Z; Chow, S Y (1995) Effects of glutamate, N-methyl-D-aspartate, high potassium, and hypoxia on unit discharges in CA1 area of hippocampal slices of DBA and C57 mice. Epilepsia 36:196-206
Wang, Z; Chow, S Y (1994) Effect of kainic acid on unit discharge in CA1 area of hippocampal slice of DBA and C57 mice. Epilepsia 35:915-21
Li, J; Chow, S Y (1994) Effects of dibutyryl cyclic AMP on Na+,K(+)-ATPase activity and intracellular Na+ and K+ in primary cultures of astrocytes from DBA and C57 mice. Epilepsia 35:20-6
Li, J; Chow, S Y (1994) Subcellular distribution of carbonic anhydrase and Na+,K(+)-ATPase in the brain of the hyt/hyt hypothyroid mice. Neurochem Res 19:83-8
White, H S; Chow, S Y; Yen-Chow, Y C et al. (1992) Effect of elevated potassium on the ion content of mouse astrocytes and neurons. Can J Physiol Pharmacol 70 Suppl:S263-8
Chow, S Y; Li, J; Woodbury, D M (1992) Water and electrolyte contents, cell pH, and membrane potential of primary cultures of astrocytes from DBA, C57, and SW mice. Epilepsia 33:393-401
Chow, S Y; Yen-Chow, Y C; Woodbury, D M (1992) Studies on pH regulatory mechanisms in cultured astrocytes of DBA and C57 mice. Epilepsia 33:775-84
Chow, S Y; Yen-Chow, Y C; White, H S et al. (1991) Effects of potassium on the anion and cation contents of primary cultures of mouse astrocytes and neurons. Neurochem Res 16:1275-83
Chow, S Y; Yen-Chow, Y C; White, H S et al. (1991) pH regulation after acid load in primary cultures of mouse astrocytes. Brain Res Dev Brain Res 60:69-78
Chow, S Y; White, H S; Yen-Chow, Y C et al. (1989) Uptakes of iodide and chloride by primary cultures of mouse astrocytes and neurons. Neurochem Res 14:963-9

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