Modulating Thyroid Hormone Levels in Adult Mice: Impact on Behavior and Compensatory Brain Changes

Figure 7

A model for the brain changes in response to hyper- and hypothyroidism. T4 circulates at a much higher concentration than T3. T4 crosses the blood-brain barrier via the astrocytic SLC01C1 transporter (OATPC1), whereas T3 enters via SLC16A2 (MCT8). T3, either transported from blood or converted from T4 by DIO2, complexes with TH receptors (THRA and THRB) in order to enter the nucleus and affect downstream gene expression. Additionally, T3 is delivered to neurons from astrocytes in order to regulate gene expression in those cells. DIO3 serves to inactivate TH (by converting to rT3 and T2). Inset box: Summary of measured changes (in black) and their theorized downstream effects (in red) that may help to maintain homeostatic TH levels in the brain during treatment. Our data indicate that, in response to thyroxine treatment, Dio3 mRNA expression is robustly increased, which would increase inactivation of TH. On the other hand, Dio2 expression decreases, which could prevent the activation of T4 to T3. Slc16a2 expression trends toward a decrease, indicating a possible reduction in transport. Slco1c1 expression is unchanged. The expression of the TH receptors decreases, reducing the potential for aberrant regulation of gene expression. The changes observed due to PTU/Met treatment are less robust, although both Dio2 and ThrA expression trends toward an increase.