IMPACT OF THYROID HORMONE TRANSPORTERS MCT8/OATP1C1 ON HIPPOCAMPAL NEUROTRANSMISSION AND SEIZURE SUSCEPTIBILITY

The monocarboxylate transporter MCT8 mediates thyroid hormone (TH) transport into brain cells and is essential for proper CNS development and function. In humans, inactivating mutations in MCT8 cause a severe psychomotor retardation associated with central TH deficiency and epileptic seizures of unknown etiology. Due to species-specific differences in the expression of TH-transporting organic anion transporting polypeptide Oatp1c1, symptoms of MCT8 deficiency can only be replicated in Mct8/Oatp1c1 double-knockout (dKO) mice. Here, we investigated the mechanisms underlying seizure susceptibility using the dKO model focusing on the hippocampus. Seizure susceptibility was assessed using the pilocarpine model, revealing a significantly reduced seizure threshold and increased seizure severity in dKO mice. Immunofluorescence analysis of hippocampi 12 h after seizure induction showed robust expression of the neuronal activation marker cFos in dKO mice, indicating sustained network hyperexcitability. To identify underlying molecular alterations, we performed unbiased LC-MS/MS proteomic analysis of hippocampal homogenates at postnatal day 120 (P120). This analysis revealed downregulation of several astrocyte-associated ion channels and transporters, including Kcnj10, Atp1a2, Atp1b2, and Slc22a2, which was confirmed by qPCR and Western blot analyses, despite pronounced astrogliosis as shown by immunofluorescence studies. Given the critical role of Kcnj10 in potassium buffering, which is required for efficient glutamate clearance, we assessed glutamate levels by LC-MS and observed increased hippocampal glutamate concentrations in adult dKO mice. Together, these findings indicate that impaired TH transport disrupts astrocytic ion and glutamate homeostasis, contributing to hippocampal hyperexcitability and increased seizure susceptibility.