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

Tiago B Rodrigues,Barbara Nuñez,Sebastian Cerdán,Samuel Refetoff,Beatriz Morte,Juan Bernal,Ainhoa Ceballos,Carmen Grijota-Martínez,Michelina Plateroti

doi:10.1371/journal.pone.0074621

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.

Highlights

Thyroid hormones [3,5,3’,5’-tetraiodothyronine (T4) and 3,3’,5triiodothyronine (T3)] play an important role in brain development and function [1,2]
As for Hr expression in the cerebral cortex, there was a significant effect of genotype, with a decrease in the Mct8KO mice (P = 0.0028), but no effect of treatment (P = 0.196)
There was a significant effect of genotype on the fractional enrichment of 13C into glutamate C4 (P,0.0001), glutamine C4 (P = 0.00275), and GABA C2 (P,0.0001), with increases in 13C labeling of the three metabolites in the mutant mice

Summary

Introduction

Thyroid hormones [3,5,3’,5’-tetraiodothyronine (T4) and 3,3’,5triiodothyronine (T3)] play an important role in brain development and function [1,2]. Thyroid hormones uptake by the target cells is facilitated by several forms of plasma membrane transporters [3]. MCT8 gene mutations cause an X-linked syndrome combining severe neurodevelopmental impairment and abnormal distribution and metabolism of thyroid hormones [6,7,8,9,10,11,12,13,14,15,16,17,18]. The syndrome manifests in infants as early as two months of age. It is characterized by truncal hypotonia evolving into spastic quadriplegia, mental retardation with severe global developmental delay, dystonic movements, lack of speech development and other signs of neurological impairment. The defective transport of thyroid hormones across cell membranes causes decreased serum concentrations of T4 and 3,3’,5’-triiodothyronine (reverse T3, rT3), and increased T3 by a complex mechanism involving hormone secretion, metabolism and excretion [11,14,19,20,21]

Methods

Results

Conclusion