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The type 3 deiodinase (D3) is an enzyme that inactivates thyroid hormones (TH) and is highly expressed during development and in the central nervous system. D3-deficient (D3KO) mice develop markedly elevated serum T(3) level in the perinatal period. In adulthood, circulating T(4) and T(3) levels are reduced due to functional deficits in the thyroid axis and peripheral tissues (i.e. liver) show evidence of decreased TH action. Given the importance of TH for brain development, we aimed to assess TH action in the brain of D3KO mice at different developmental stages and determine to what extent it correlates with serum TH parameters. We used a transgenic mouse model (FINDT3) that expresses the reporter gene β-galactosidase (β-gal) in the central nervous system as a readout of local TH availability. Together with experiments determining expression levels of TH-regulated genes, our results show that after a state of thyrotoxicosis in early development, most regions of the D3KO brain show evidence of decreased TH action at weaning age. However, later in adulthood and in old age, the brain again manifests a thyrotoxic state, despite reduced serum TH levels. These region-specific changes in brain TH status during the life span of the animal provide novel insight into the important role of the D3 in the developing and adult brain. Our results suggest that, even if serum concentrations of TH are normal or low, impaired D3 activity may result in excessive TH action in multiple brain regions, with potential consequences of altered neural function that may be of clinical relevance to neurological and neuroendocrine disorders.

Type 3 Deiodinase Deficiency Causes Spatial and Temporal Alterations in Brain T3 Signaling that Are Dissociated from Serum Thyroid Hormone Levels