Endocrine Abstracts

Inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in a severe form of psychomotor retardation (known as Allan-Herndon-Dudley syndrome, AHDS) due to compromised TH access to the CNS. Consequently, TH-dependent processes both during brain development and in the adult CNS such as adult hippocampal neurogenesis are impaired. Using mice deficient in Mct8, we recently demonstrated a diminished neurogenesis in the adult hippocampus due to combined cell-autonomous and non-autonomous requirements for Mct8. To further investigate alterations in adult neurogenesis in Allan-Herndon-Dudley syndrome, we addressed the question whether T4-specific organic anion transporting polypeptide 1c1 (Oatp1c1) acts in concerts with Mct8 in regulating adult neurogenesis in Mct8/Oatp1c1 double knockout (dko) mice, the currently most suitable mouse model for AHDS. We first defined Oatp1c1 expression in a subset of hippocampal progenitor cells and granule cell neurons. Then, analysing distinct stages within the cell lineage leading to adult hippocampal neurogenesis in Mct8/Oatp1c1 dko and single transporter mutant mice by immuno-histochemistry, we showed that Mct8/Oatp1c1 dko mice replicated the impaired neuroblast differentiation and neuron formation capacity previously attributed to cell-autonomous Mct8 function. In addition, however, we demonstrated that absence of Oatp1c1 results in a further increase in the number of earlier progenitor cells within the lineage (stage 2 and stage 3 cells) at 6 months of age. Importantly, in all knockout models, we observed selective impairments in hippocampus-related functions and a depression-anxiety like phenotype in the open field arena. Together, our results point to a function of Oatp1c1 in the adult hippocampal neurogenic programme and substantiate the concept that TH transport is required at multiple levels in this process.