Since seizures are intermittent, yet the underlying stimulus is constantly present, it is evident that the seizure discharge must be set off by some initiating factor. It is the purpose of this project to define the hormonal factors that increase or decrease seizure-susceptibility. The main objective is to delineate the role of thyroid hormones in altering susceptibility of the brain to experimentally-induced seizures and to determine the site and mechanisms involved in their action. The major thrust is to determine the role of thyroid hormone in brain development and aging from a neurophysiological and neurochemical standpoint. The main hypothesis to be tested is that thyroid hormone affects the susceptibility of the brain to seizures through alteration of cation and anion transport processes in neurons and glia by regulating the activities of the enzymes involved in these transport processes, namely, Na+, K+-ATPase, Ca++, Mg++-ATPase, HC03--ATPase, and carbonic anhydrase. A key role of thyroid hormone appears to be regulation of anion transport via the mitochondrial enzyme, HC03--ATPase, and the cytosolic and membrane-bound enzyme, carbonic anhydrase, during early development and during initiation of glial cell growth. This enzyme appears to trigger the development of these two cell types. Therefore, in the absence of adequate thyroid hormone during a critical period of maturation, the development of HC03--ATPase activity in both neurons and glia is delayed with the resultant anatomical and biochemical alterations in brain characteristic of the hypothyroid state that lead to increased seizure susceptibility. Preliminary observations support this hypothesis. Thus, the activity of HC03--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, neuropharmacological, and immunochemical approaches both in vivo and in vitro by the use of isolated glial cells in culture. The activity of transport enzymes, the concentration of electrolytes, measured by chemical analysis and by use of ion-selective double barrelled microelectrodes (K+, C1-, Na+, and H+) and the analysis of DNA and protein will be determined in hypothyroid and hyperthyroid states and correlated with thyroxine levels in plasma and changes in brain excitability during maturation. Since hypothyroidism in infants produces cretinism, understanding the processes by which this occurs is of great importance in the clinical control of this disease.
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