Thyroid hormone receptors (TR) are expressed throughout the forebrain of the developing and adult rat. There are two gene products, TR alpha and TR beta, each of which has several alternately spliced variants. TR alpha 1 binds thyroid hormone, whereas the TR alpha 2 splice variant does not; TR beta 1 and TR beta 2 have identical sequences in their DNA-binding, hinge-region, and ligand-binding domains and differ only at the amino terminal region as a result either of alternative splicing or alternative promotor usage (Lechan et al., 1993). In adult life, TR alpha 1 and TR alpha 2 mRNA are expressed at similar levels in olfactory bulb, hippocampus, and granular layer of the cerebellar cortex, whereas TR beta mRNAs were concentrated in the anterior pituitary and parvocellular paraventricular nucleus (Bradley, Young, and Weinberger, 1989). A related mRNA, REV-ErbA alpha, which fails to bind thyroid hormone, was concentrated in the cerebral cortex (Bradley, Towle, and Young, 1992; Bradley, Young, and Weinberger, 1989). In contrast to the mRNA, immunoreactivity for the TR beta 2
protein was expressed in cerebral cortex, cerebellum, and hypothalamus in areas where the mRNA had not been identified (Lechan et al., 1993). Likewise, TR beta 1 immunoreactivity was found widely expressed in the forebrain, with highest levels in cerebral cortex, particularly parietal cerebral cortex layer 1, olfactory bulb, and hippocampus; thyroidectomy resulted in increased immunoreactivity in a number of brain regions, particularly in habenula and the CA3 region of the hippocampus (Nobrega et al., 1997).
In the developing brain, TR beta 2, which binds to adult anterior pituitary, is expressed in developing hippocampus and striatum, whereas TR alpha 1 and TR alpha 2 mRNAs are expressed in the fetal neocortical plate where there is active neurogenesis (Bradley, Towle, and Young, 1992). Hyperthyroidism early in neonatal life alters hippocampal morphology and the neurochem-istry and structure of the basal forebrain cholinergic system of rats (Gould, Woolley, and McEwen, 1991; Westlind-Danielsson, Gould, and McEwen, 1991). In spite of these effects, sex differences in these systems persist in both basal forebrain and hippocampus (Gould, Westlind-Danielsson, et al., 1990; Westlind-Danielsson, Gould, and McEwen, 1991). The same was true for morphological changes in the dendrites of CA3 pyramidal neurons: Hyperthyroid animals had more thorny excrescences in stratum lucidum and longer and more extensively branched apical dendrites (Gould, Westlind-Danielsson, et al., 1990). Astroglial cells in the basal forebrain and septal area were also larger and more extensively branched (Gould, Frankfurt, et al., 1990).
But this hypertrophy is not necessarily to the benefit of the treated animal. On one hand, in the rat experiments cited earlier, both male and female hyperthyroid animals are slower to acquire a hippocampal-dependent spatial learning task and are somewhat impaired in showing long-term potentiation in the hippocampus (Pavlides et al., 1991). On the other hand, a strain of mice that normally shows poor spatial learning and may have a congenital deficiency of thyroid hormone secretion during early development displays a beneficial effect of the same kind of neonatal thyroid hormone treatment (Schwegler et al., 1991). Thus there is an optimal level of thyroid hormone that is associated with optimal cognitive performance, and deviations in the direction of both hyper- and hypothyroidism result in deficiencies in neural development and cognitive function.
A hyperthyroid state in adult life, induced by repeated thyroid hormone treatment, produced morphological alterations in hippocampal pyramidal neurons, involving a reduction in spine density (Gould, Allan, and McEwen, 1990), which is different from and opposite to the effects described for hyperthyroidism in the neonatal rat brain. Like sexual differentiation, described earlier, this is one more example of how the effects of hormones change as the brain matures.
Changes in response to thyroid hormones have been studied in hippocampus as a function of developmental age. In the CA3 region, the main effect of hypothyroid-ism involved decreases in volume of the pyramidal cell layer and increases in packing density of pyramidal neurons without reductions in neuronal number (Madeira et al., 1992). These effects were evident whether the hy-pothyroid condition was during the first 30 days of neonatal life, or between 30 and 180 days, or for the entire 180-day period (Madeira et al., 1992). In the CA1 region, however, there was evidence of neuronal loss (Madeira et al., 1992).
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