Increased Oxidative Metabolism and Neurotransmitter Cycling in the Brain of Mice Lacking the Thyroid Hormone Transporter Slc16a2 (Mct8)

Abstract

Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T4 and T3) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T4 and T3. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-13C) glucose and brain extracts prepared and analyzed by 13C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood.

Altered Behavioral Performance and Live Imaging of Circuit-Specific Neural Deficiencies in a Zebrafish Model for Psychomotor Retardation

“…In order to elucidate the pathophysiological mechanisms of AHDS, an MCT8 knockout (KO) mouse model was generated. These KO mice replicate the endocrine and metabolic abnormalities found in human patients [9] – [12] . However, they did not display any neurological or behavioral phenotypes.…”

Failure of thyroid hormone treatment to prevent inflammation-induced white matter injury in the immature brain

“…The clinically relevant dose of T4 for the neonatal mouse is unknown, however the dose used in this study maintains the normal physiological levels of T4 when administered to adult hypothyroid mice (Rodrigues et al, 2013). Euthyroid treatment is critical as overexposure to TH may have negative effects on the brain (Nicholson and Altman, 1972), and TH repression of TSH can cause hypothyroidism upon completion of therapy (La Gamma et al, 2009).…”

Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish

“…In order to study the mechanism underlying AHDS, an Mct8 knockout ( Mct8 -KO) mouse model was established. Similar to individuals with AHDS, the Mct8 -KO mice showed altered TH levels in the serum; however, neurological and behavioral phenotypes were not apparent (Di Cosmo et al, 2013; Dumitrescu et al, 2006; Rodrigues et al, 2013; Trajkovic et al, 2007). This might be explained by a compensation mechanism in mice in which the organic anion transporting polypeptide 1C1 ( Oatp1c1 ), a T4-selective transporter, is predominantly expressed in the BBB (Ito et al, 2011; Mayerl et al, 2012; Roberts et al, 2008).…”