Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain

Abstract

Monocarboxylate transporter 8 (MCT8) and organic anion transporter polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters that play an important role in the availability of TH for neural cells, allowing their proper development and function. It is important to define which cortical cellular subpopulations express those transporters to explain why MCT8 and OATP1C1 deficiency in humans leads to dramatic alterations in the motor system. By means of immunohistochemistry and double/multiple labeling immunofluorescence in adult human and monkey motor cortices, we demonstrate the presence of both transporters in long-projection pyramidal neurons and in several types of short-projection GABAergic interneurons in both species, suggesting a critical position of these transporters for modulating the efferent motor system. MCT8 is present at the neurovascular unit, but OATP1C1 is only present in some of the large vessels. Both transporters are expressed in astrocytes. OATP1C1 was unexpectedly found, only in the human motor cortex, inside the Corpora amylacea complexes, aggregates linked to substance evacuation towards the subpial system. On the basis of our findings, we propose an etiopathogenic model that emphasizes these transporters’ role in controlling excitatory/inhibitory motor cortex circuits in order to understand some of the severe motor disturbances observed in TH transporter deficiency syndromes.

Thyroid Hormone Transporters MCT8 and OATP1C1 are Expressed in Projection Neurons and Interneurons of Basal Ganglia and Motor Thalamus in the Adult Human and Macaque Brain

“…In agreement with the previous findings at the protein level by IHC [25,56,[58][59][60], we observed the cellular expression pattern of MCT8 in the endothelial cells of vessels, and we demonstrate for the first time the expression of MCT8 in basal ganglia pericytes and the expression of MCT8 and OATP1C1 in monkey choroid plexus.…”

“…Additionally, some abundantly scattered fibers in the striatum showed MCT8 immunoreactivity in both humans and macaques. In the human brain sections, we have observed that there are aggregations of Corpora amylacea surrounding the lateral ventricles (Figure S2) which is consistent with our previous finding in the human cortex [25]. We also found some OATP1C1 immunoreactive depositions restricted to striatum gray matter neuropil and not present in white matter, in all seven human individuals under the antigen retrieval free condition (Figure S2).…”

“…The selection of specific antibodies was a critical challenge for this study. The quality and specificity of the primary antibodies used in this work have been verified and discussed in previous articles [25,[56][57][58]. The individual variability of the sample and the differences in antibodies might be the reason why most of the human anatomy and histology insights reported in the literature for the MCT8 and OATP1C1 distribution in the basal ganglia are either incomplete or ambiguous.…”

“…In any case, even if the expression of these transporters had been altered by non-thyroidal illness syndrome in our human tissue, they were still present and both showed a similar immunocytochemical signal in the subpopulations of cells described in the paper, as we have demonstrated consistently, in all the studied brains. Concerning the deleterious effect of the postmortem human brain tissues on antigenicity, we have taken great care to optimize protocols to eliminate non-specific staining, autofluorescence, and false negatives in order to yield reliable results, as explained in a previous paper [25]. For the same reasons stated above, we only conducted a qualitative study and did not conduct a quantitative study.…”

“…In previous work, we have discussed the alterations of the cerebellum in AHDS patients [20] as a possible underlying factor for motor disturbances. We have also discussed the possible implications of the lack of expression of MCT8 and OATP1C1 in cortical projection neurons and interneurons of adult human and monkey brain [25]. Here we focus on the distribution of TH transporters in the basal ganglia.…”