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Research Article: Neuron-specific expression of murine thyroid hormone transporters Mct8 and Oatp1c1 is dispensable for hippocampus-dependent neuronal functions

Date Published: 2026-03-17

Abstract:
Global absence of the thyroid hormone (TH) transporters monocarboxylate transporter 8 (Mct8) and organic anion transporting polypeptide 1c1 (Oatp1c1) in Mct8/Oatp1c1 double knockout (M/O dKO) mice results in a severe central TH deficit due to impaired TH transport across brain barriers. This deficit is accompanied by pronounced abnormalities in inhibitory and excitatory neuronal systems in the brain. However, it remains unclear whether these alterations arise solely from central TH deficiency or whether Mct8 and Oatp1c1 also exert cell-autonomous functions in neurons. Immunofluorescence and fluorescent in situ hybridization (FISH) were used to first characterize the expression of Mct8 and Oatp1c1 in GABAergic interneuron subpopulations. Two conditional mouse lines with deletion of both transporters either in all GABAergic (GABA del mice) or glutamatergic neurons (Glut del mice) were then generated. Serum TH concentrations and TH-dependent gene expression were assessed by LC–MS/MS and FISH, respectively. Using immunofluorescence and qPCR, components of the GABAergic and glutamatergic systems as well as adult hippocampal neurogenesis were evaluated. Functional analyses were performed including pilocarpine-induced seizure susceptibility, novel object recognition and elevated plus maze tests. Serum TH concentrations and TH-regulated gene expression in the brain were unaltered in both conditional mouse lines. No differences in GABAergic markers and expression of glutamatergic ionotropic receptor subunits were found in the hippocampus of GABA del and Glut del mice alongside a normal seizure susceptibility and an unaltered neurogenic program in the adult dentate gyrus. Finally, evaluation of hippocampus-dependent behaviors did not reveal alterations upon neuronal Mct8/Oatp1c1 deficiency, whereas M/O dKO mice exhibit abnormal anxiety-related behavior. Together, these data point to the central hypothyroid state of M/O dKO mice as the main cause of the neuronal alterations present in these animals and rule out a major cell-autonomous function of Mct8/Oatp1c1 in GABAergic or glutamatergic neurons.

Introduction:
Global absence of the thyroid hormone (TH) transporters monocarboxylate transporter 8 (Mct8) and organic anion transporting polypeptide 1c1 (Oatp1c1) in Mct8/Oatp1c1 double knockout (M/O dKO) mice results in a severe central TH deficit due to impaired TH transport across brain barriers. This deficit is accompanied by pronounced abnormalities in inhibitory and excitatory neuronal systems in the brain. However, it remains unclear whether these alterations arise solely from central TH deficiency or whether Mct8 and…

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