Leung, Feng Chiao Lilian; (1995) Effects of hypothyroidism on cell signalling in the developing rat brain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Rat pups born of dams maintained on a propylthiouracil/low iodine diet regime were used to assess the effects of hypothyroidism on signalling components in the developing brain. The success of the animal model of perinatal hypothyroidism was confirmed following measurements of free T3 and T4 plasma levels. Alterations in development and behaviour noted in hypothyroid pups were similar to those observed previously by other groups. Plasma metabolite concentrations indicated that the impairments in body and brain development noted in the hypothyroid state, were not the result of serious under-nutrition. Crude and synaptosomal membranes were isolated from forebrain and hindbrain regions of euthyroid and hypothyroid animals at various ages. Changes in α-subunit abundance of Gq, Gq, Gjl and Gi2 were measured viaquanlitative immunoblotting. No differences in a-subunit levels of euthyroid and hypothyroid crude membranes were seen in either brain region. Compared to euthyroid animals, between 10 and 20 days postpartum a number of significant alterations were detected in synaptosomal membranes isolated from forebrains of hypothyroid pups; with the exception of Gi2α, all of these changes were that of subunit up-regulation. By contrast, the hindbrain showed very few hypothyroid-induced changes; the only significant effects were seen in Gilα at day 10 (total hindbrain) and day 25 (medulla oblongata). Hypothyroidism also altered the normal developmental profiles of all four α-subunits in both forebrain and hindbrain regions. Synaptosomal membranes of 15 day old pups were also used to assess hypothyroid-induced effects on adenylyl cyclase activity. Changes in the pattern of activation/inhibition of adenylyl cyclase by GTP were observed in hypothyroid forebrain and hindbrain membranes in the presence of forskolin. Furthermore, a significant decrease in specific cyclase activity was observed in hypothyroid forebrain membranes. By contrast, in the hindbrain, a significant increase in cyclase activity was evident. Together, the changes observed may contribute to some of the neurological defects seen during perinatal hypothyroidism.

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