Endocrine Abstracts

Thyroid hormone (TH) action is required for the adequate brain development. While TRα1 is recognized as the predominant receptor mediating most of these effects in brain tissue, the expression of both TRα and TRβ during development prompts further examination on their respective role. The study aims to investigate the role of TRβ during cortical neuron differentiation, taking advantage of induced pluripotent stem cells (iPSCs) obtained from patients with resistance to thyroid hormone β (RTHβ) who exhibit variable neurocognitive/behavioral defects. To achieve this, peripheral blood mononuclear cells (PBMCs) from RTHβ patients with anxiety and/or severe short-term memory defects, or from healthy individuals, were expanded and reprogrammed into iPSCs that were then differentiated into cortical neurons using a validated protocol. Quantitative real-time PCR analysis was conducted on the resulting cortical progenitors and neurons. The findings revealed expression of THRB transcripts, with a ratio of 1:2 relative to THRA, supporting the potential involvement of TRβ in the neurological development. Then, we detected differences in the expression levels of various neural markers related to synaptic plasticity and the complex molecular mechanisms underlying learning and memory, such as Neuroplastin and Neurexin, in cortical neurons derived from RTHβ patients compared to those from controls. Additionally, a marked decrease was seen in the expression levels of vesicular glutamate transporters (VGLUT1 and VGLUT2) in the RTHβ samples. Intriguingly, studies in animal models linked VGLUT1 deficiency to deficits in visual attention, anxiety, and depression, while the expression of VGLUT1/2 correlated with learning and memory processes. Interestingly, electrophysiological experiments demonstrated that only the THRB mutant neurons failed to generate action potentials. This study reveals critical differences in several biomarkers of neuronal development and function in neurons differentiated from RTHβ iPSCs. The contribution of TRβ to TH action in the developing brain might be underestimated. This study is partially founded by the project ADAM-THAD (PNRR-MR1-2022-12375726).