Thyroxine, Triiodothyronine, and Reverse Triiodothyronine Processing in the Cerebellum: Autoradiographic Studies in Adult Rats*

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Abstract
Well-confirmed evidence has demonstrated that the cerebellum is an important target of thyroid hormone action during development. Moreover, the presence of nuclear receptors and strong 5''-deiodinase activity in cerebella of adult rats have suggested that this region may continue to respond to thyroid hormones during maturity. Recent autoradiographic observations have forced attention on the cerebellar granular layer, in that [125I]T3 administered iv to adult rats was found to be selectively and saturably concentrated there. To determine the specificity of iodothyronine localization in the granular layer, we have now compared film autoradiographic observations made after iv [125I]T4 and iv [125I]T3 with those found after iv [125I]T3. The results demonstrated that, as in the case of the latter hormone, labeling within the cerebellar cortex after iv [125I]T4 was both selective and saturable. Moreover, except for a lag in time to resolution and a longer retention time, the distribution of cerebellar radioactivity after iv labeled T4 was qualitatively similar to that seen after iv [125I]T3. However, the ability of T4 to become differentially concentrated in the granular layer of cerebellum was absolutely dependent on its ability to be converted intracerebrally to T3. Thus, pretreatment with ipodate, which blocks brain 5''-deiodinase activity and, therefore, the intracerebral formation of T3 from T4, completely prevented cerebellar granular layer labeling after iv [125I]T4 even though it did not interfere with differential labeling of this region by iv delivered [125I]T3. In the same experiments, propylthiouracil, a potent peripheral, but not central, 5''-deiodinase inhibitor, had no qualitative effect on the distribution of either T4 or T3 in cerebellum. By contrast with the results obtained after administering labeled T3 or T4, brain labeling after iv delivered [125I]rT3 was found to be no different from that produced by markers of cerebral blood flow, which rapidly enter and leave the brain without becoming incorporated into brain cells. This was so even during treatment with propylthiouracil and ipodate, both of which markedly prolonged the normally brief residence time of this iodothyronine in serum and brain. Overall, the autogradiographic results served to highlight the importance of the morphological approach for investigating thyroid hormone action and metabolism in brain. They demonstrated that only T3, whether entering as such from the circulation or formed in situ from T4 (but neither T4 itself nor iv administered rT3) was strongly, selectively, and saturably concentrated in the cerebellar granular layer of adult rats. The high degree of iodothyronine specificity as well as morphological specificity revealed by these studies suggest that constituents of the granular layer may be important histological sites of putative thyroid hormone actions in both developing and adult cerebellum.