THE COMBINATION OF L-THYROXINE AND 3-IODOTHYRONAMINE ENHANCES HIPPOCAMPAL NEUROGENESIS IN A MURINE MODEL OF HYPOTHYROIDISM

Adult‐onset hypothyroidism is associated with cognitive perturbations, depression and anxiety, pointing to an underlying disruption of hippocampal plasticity. Symptoms usually remit after L‐thyroxine (L‐T4) replacement. However, about 5‐10% of hypothyroid patients do not achieve satisfactory functional levels. Tissue levels of TH metabolites, such as 3‐iodothyronamine (T1AM), are also decreased in hypothyroidism, and remain low after L‐T4 replacement. As T1AM has pro‐learning effects, we hypothesize that its reduced availability may impact neurocognition and related neurobiological alterations. We sought to assess the impact of alternative replacement therapies on hippocampal neurogenesis in a pharmacologically induced hypothyroidism model. Six‐week‐old C57BL/6J male mice (n = 12) were given Methimazole and Potassium Perchlorate (0,20 mg/g/die and 0,30 mg/g/die) in drinking water for 49 days while the control littermates (n = 3) received water. At day 21, mice were implanted with subcutaneous ALZET® osmotic pumps delivering replacement treatments for 28 days. Animals were divided in 5 groups: euthyroid (n = 3); hypothyroid (n = 3); LT4 (n = 3); LT4&T1AM (n = 8); T1AM (n = 3). To assess neurogenesis in the sub granular zone (SGZ) of the dentate gyrus, we performed immunofluorescence for specific markers, such as Ki67 for cell proliferation and doublecortin (DCX) for newborn neuroblasts and immature neurons. Images were captured using a Leica confocal microscope (SP8) and analysis was performed using Fiji. The number of DCX+ cells obtained from 4 coronal sections (‐1.82 mm to ‐2.36 mm from bregma, 180 μm interval) was summed to obtain a single estimate per mouse. A 49‐day period of adult‐onset hypothyroidism induced a reduction of around 20% in the number of DCX+ newly generated cells. L‐T4 replacement restored the number of DCX+ cells (116% of euthyroid), which was further increased by the combination of L‐T4 and T1AM (137% of euthyroid), while T1AM did not show any effect per se. One‐way ANOVA revealed a global significant effect among the 5 groups (F (4, 10) = 3.97, p = 0.03). These results, as long as preliminary, suggest that T1AM, alongside canonical TH, modulates adult hippocampal neurogenesis. Future studies should elucidate whether L‐T4&T1AM combination may improve hypothyroid patients' cognitive dysfunctions and prevent the neurodegenerative consequences of hypothyroidism.