Neural alterations and hyperactivity of the hypothalamic–pituitary–thyroid axis in Oatp1c1-deficiency

Thyroid hormones (THs) T3 and T4 are crucial regulators of brain development and function. Cell-specific transporter proteins facilitate TH uptake and efflux across the cell membrane, and insufficient TH transport causes hypothyroidism and mental retardation. Mutations in the TH transporters monocarboxylate transporter 8 (MCT8, SLC16A2) and the organic anion-transporting polypeptide 1C1 (OATP1C1, SLCO1C1) are associated with the psychomotor retardation Allan-Herndon-Dudley syndrome (AHDS) and juvenile neurodegeneration, respectively. In order to understand the mechanisms and test potential treatments for the recently discovered OATP1C1-deficiency, we established an oatp1c1 mutant (oatp1c1-/-) zebrafish. oatp1c1 is expressed in endothelial cells, neurons, and astrocytes in zebrafish. The activity of the hypothalamic–pituitary–thyroid (HPT) axis and behavioral locomotor activity increased in oatp1c1-/- larvae. Neuropathological analysis revealed structural alteration in radial glial cells and shorter neuronal axons in oatp1c1-/- larvae and adults. Notably, oatp1c1-/- and oatp1c1-/-Xmct8-/- adults exhibit an enlarged thyroid gland (goiter). Pharmacological assays showed that TH analogs, but not THs, can normalize the structure of the thyroid gland in adult zebrafish. These results establish a vertebrate model for OATP1C1-deficiency that demonstrates endocrinological, neurological, and behavioral alterations mimicking the patient`s symptoms. Furthermore, the curative effect of TH analogs in the oatp1c1-/- zebrafish model provides a promising treatment direction for patients.