Adult cerebellar thyroid hormone signalling: molecular, structural, and behavioural effects of sobetirome in wildtype and Mct8/Dio2 double knockout mice

• Grant number: 25/23289-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: February 28, 2026
• End date: February 27, 2027
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Maria Tereza Nunes
• Grantee: Johnatas Maldonado Campos
• Supervisor: Ana Guadaño Ferraz
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Consejo Superior de Investigaciones Científicas (CSIC), Spain
• Associated to the scholarship: 22/12190-8 - Caracterisation of the action of triiodothyronine (T3) and the thyromimetic sobetiramide (Sob-AM2) in the hippocampal formation of Wistar rats with Diabetes induced by alloxan, BP.DD

Abstract

Thyroid hormones (THs, T4 and T3) regulate CNS development and adult function, mainly by modulating gene transcription via binding to specific nuclear receptors. MCT8 is a critical TH transmembrane transporter, and its deficiency causes Allan-Herndon-Dudley Syndrome (AHDS), characterised by brain hypothyroidism and peripheral thyrotoxicosis. The thyroid gland synthetises mainly T4 and in the brain, DIO2 locally converts T4 to the transcriptionally active T3, and combined loss of MCT8 and DIO2 severely impairs cerebral TH signalling. The Mct8/Dio2 double knockout mouse models profound central hypothyroidism. Sobetirome, a TH analogue with thyromimetic properties, crosses the blood-brain barrier and modulate cerebral TH signalling. This project investigates the effects of sobetirome in adult cerebellum, in wild-type and Mct8/Dio2 knockout mice. Molecular outcomes will be assessed by RT-qPCR analyses of TH target genes and neuroplasticity markers. Structural analyses will characterise cerebellar cytoarchitecture, neuronal populations, and synaptic markers via immunohistochemistry and immunofluorescence. Functional effects will be evaluated using Rotarod and Open Field tests. By integrating molecular, structural, and behavioural approaches, the project addresses a critical gap in adult cerebellar TH biology. Findings will complement ongoing doctoral research and inform translational strategies for brain hypothyroidism and MCT8-deficiency. (AU)