Sustained neonatal hyperthyroidism in the rat affects myelination in the central nervous system

Abstract

We have carried out a study of the effects of sustained neonatal hyperthyroidism on myelin and on the oligodendroglial cells, in an effort to obtain further insight into the molecular mechanisms underlying the action of thyroid hormones on the central nervous system (CNS). Expression of the mRNAs of myelin basic protein (MBP) myelin proteolipid protein (PLP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), transferrin, and c-Jun was investigated in 10- and 17-day-old normal and hyperthyroid rats, using Northern blot analysis. At 10 days of age, the levels of all the explored mRNAs were markedly higher in the experimental animals. The mRNA of transferrin showed a ninefold increase over control values, suggesting the possibility that this putative trophic factor might act as one of the mediators in the action of thyroid hormones. At 17 days of age on the other hand, the levels of all the mRNAs decreased markedly, reaching values below control, except for c-Jun, which remained higher than in normals. At 70 days of age, hyperthyroid rats showed clear evidence of myelin deficit, in agreement with previous results of our laboratories (Pasquini et al.: J Neurochem 57: Suppl S124, 1991). Immunocytochemistry of 70-day-old rat brain tissue sections showed a substantial reduction in the amount of MBP-reacting structures and a marked decrease in the number of oligodendroglial cells. Although the above-mentioned results could be the consequence, as proposed by Barres et al. (Development 120:1097-1108, 1994) and Baas et al. (Glia 19:324-332, 1997) of a premature arrest in oligodendroglial cell proliferation followed by early differentiation, the persistent high levels of expression of c-Jun, together with the dramatic decrease in the number of oligodendrocytes, suggested the possibility that prolonged hyperthyroidism could activate apoptotic mechanisms in the myelin forming cells. Using propidium iodide-labeled isolated oligodendroglial cells, we found, by flow cytometry, a significant increase in the number of apoptotic/hypo-diploid propidium iodide-positive cells. These results indicate that one of the actions of sustained levels of thyroid hormones in the neonate rat is to increase oligodendroglial cell death by apoptosis.

Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors.

“…Moreover, A1254 exerted selective effects on the expression of TH-responsive genes because NSP-C, which is not influenced by TH in the fetus (Dowling et al , 2001, was not affected by A1254. Furthermore, previous work in our laboratory has demonstrated that A1254 increases the expression of myelin basic protein, a known TH-responsive gene (Farsetti et al 1991;Marta et al 1998;Rodriguez-Pena et al 1993), in the cerebellum and RC3/neurogranin in the forebrain of postnatal rats, despite the finding that these pups exhibited a Article | Gauger et al Assays were performed to determine whether PCBs present in A1254 were able to alter the affinity TRs for T 3 . Isolated nuclei were incubated with 1.0 nM 125 I-T 3 , and increasing concentrations (1 × 10 -12 M to 1 × 10 -6 M) of T 3 alone or with increasing concentrations (1 × 10 -12 M to 1 × 10 -6 M) of T 3 in the presence of 20 µM of the PCB competitor.…”

Thyroid hormone, brain development, and the environment.

“…During the first 3 postnatal weeks in the rat and mouse, two genes have been most extensively studied for their responsiveness to thyroid hormone: RC3/neurogranin in the forebrain and myelin basic protein (MBP) in the cerebellum (138)(139)(140)(141). The expression of both of these genes is up-regulated by thyroid hormone (139,142).…”

Roles for p53 and p73 during oligodendrocyte development

“…Myelination, for example, is delayed in hypothyroid animals (Dussault and Ruel, 1987;Rodriguez-Pena et al, 1993) and accelerated in hyperthyroid animals (Marta et al, 1998;Walters and Morell, 1981). Moreover, perinatal hypothyroidism decreases the number of oligodendrocytes in the optic nerve of the rat (Ibarrola et al, 1996) and mouse (Ahlgren et al, 1997).…”