The affinity of transthyretin for T3 or T4 does not determine which form of the hormone accumulates in the choroid plexus

Abstract

Normal development of the brain is dependent on the required amounts of thyroid hormones (THs) reaching specific regions of the brain during each stage of ontogeny. Many proteins are involved with regulation of TH bioavailability in the brain: the TH distributor protein transthyretin (TTR), TH transmembrane transporters (e.g. MCT8, MCT10, LAT1, OATP1C1) and deiodinases (D1, D2 and D3) which either activate or inactivate THs. Previous studies revealed that in mammals, T₄, but not T₃, accumulated in the choroid plexus and then entered the cerebrospinal fluid. In all mammalian species studied so far, TTR binds T₄ with higher affinity than T₃, whereas TTR in non-mammalian vertebrates binds T₃ with higher affinity than T₄. We investigated if the form of TH preferentially bound by TTR influenced the form of the TH that accumulated in the choroid plexus and consequently other areas of the brain. We measured the mRNA levels corresponding to TTR, MCT8, MCT10, LAT1, OATP1C1, D1, D2 and D3 in the brains of chickens at 11days post-hatching. TTR, D3 and OATP1C1 expression were found to be highly concentrated in the choroid plexus. D1, MCT8 and MCT10 mRNA levels were slightly greater in the choroid plexus than in other areas of the brain while D2 mRNA levels were lower. LAT1 mRNA was evenly expressed throughout the brain. Therefore, the choroid plexus appears to be a structure which exhibits sophisticated control of TH levels within the brain. We also measured the uptake of intravenously injected ¹²⁵I-T₃ and ¹²⁵I-T₄ into brains of chickens of the same age. ¹²⁵I-T₄ but not ¹²⁵I-T₃ accumulated in the choroid plexus and optic lobes. Therefore, the form of TH preferentially bound by TTR does not determine the form of TH that accumulates in the choroid plexus and other areas of the brain. As for mammals, T₃ present in the avian brain therefore seems mainly produced locally by conversion of T₄ into T₃ by D2.

Keywords: Brain; Chicken; Choroid plexus; Thyroid hormone; Thyroid hormone transmembrane transporters; Transthyretin.