Thyroid hormones, t3 and t4, in the brain

Abstract

Thyroid hormones (THs) are essential for fetal and post-natal nervous system development and also play an important role in the maintenance of adult brain function. Of the two major THs, T4 (3,5,3',5'-tetraiodo-l-thyronine) is classically viewed as an pro-hormone that must be converted to T3 (3,5,3'-tri-iodo-l-thyronine) via tissue-level deiodinases for biological activity. THs primarily mediate their effects by binding to thyroid hormone receptor (TR) isoforms, predominantly TRα1 and TRβ1, which are expressed in different tissues and exhibit distinctive roles in endocrinology. Notably, the ability to respond to T4 and to T3 differs for the two TR isoforms, with TRα1 generally more responsive to T4 than TRβ1. TRα1 is also the most abundantly expressed TR isoform in the brain, encompassing 70-80% of all TR expression in this tissue. Conversion of T4 into T3 via deiodinase 2 in astrocytes has been classically viewed as critical for generating local T3 for neurons. However, deiodinase-deficient mice do not exhibit obvious defectives in brain development or function. Considering that TRα1 is well-established as the predominant isoform in brain, and that TRα1 responds to both T3 and T4, we suggest T4 may play a more active role in brain physiology than has been previously accepted.

Keywords: T3 thyronine; T4 thyronine; brain; coregulator; deiodinase 2; thyroid hormone receptor.

Figure 1

Thyroid hormone synthesis. The thyroid gland makes both T₄ and T₃, although T₄ predominates. The hypothalamus senses low TH in the circulation and responds by stimulating synthesis and secretion of TRH (thyroid releasing hormone), which in turn circulates and stimulates synthesis and secretion of TSH (thyroid stimulating hormone) by the pituitary. Circulating TSH then increases T₄ and T₃ production by the thyroid and ultimately in the circulation. Tissue-specific deiodinases (“DIO”) are expressed in peripheral tissues such as brain astrocytes to increase local concentrations of T₃ from circulating T₄. However, we propose that T₄ may also act directly on TRs to regulate gene transcription in neurons in the absence of deiodinase 2 conversion to T₃.

Figure 2

Entry of TH into brain via the blood–brain barrier. TH can enter neurons by two pathways. The first is by crossing the endothelial cells of the blood–brain barrier (BBB) by the OAT1P1C transporter to enter astrocyte end feet (in red). After entering astrocytes, T₄ can be converted into T₃ via deiodinase 2, to enter the neuron (in blue) by the MCT8 transporter. Circulating T₄ and T₃ may also enter neurons (and astrocytes) directly via these transporters through gaps in the astrocyte end feet. Oligodendrocytes (purple), which express TRs, are also known TH cell targets in the CNS. There is also evidence of as-yet unknown TH transporters in the brain; the TH transporters, and their known preferences for T₄ or T₃, are indicated in color codes on the right.