Endocrine Abstracts

Inactivating mutations in highly specific thyroid hormone (TH) transporter MCT8 result in a severe form of psychomotor retardation characterized by neurological impairments and frequent epileptic seizures of unknown etiology. These symptoms are thought to be a consequence of impaired central TH uptake across brain barriers and/or into neural cells. Mct8/Organic anion transporting polypeptide 1c1 double knockout (M/O-dKO) mice replicate characteristics of human MCT8 deficiency. Here, we aim to investigate the mechanisms underlying the seizure susceptibility in MCT8 deficient patients by studying the hippocampus of M/O-dKO mice in more detail, a brain area involved in many forms of epilepsy. We first performed a detailed characterization of inhibitory GABAergic interneurons by immunofluorescence during early postnatal development at P12 and in adulthood (P120). At P12, we detected a reduction in the general GABAergic marker glutamate decarboxylase 67 in M/O-dKO mice, a decrease in parvalbumin, and an increase in somatostatin positive cells that both label different subtypes of inhibitory interneurons. While these differences were no longer present at P120, a pronounced increase in calretinin positive mossy cell numbers, the major excitatory neuronal subtype in the hilus of the dentate gyrus, was observed in adult M/O-dKO mice only. Moreover, qPCR analysis of whole hippocampus homogenates revealed alterations in the expression of excitatory glutamatergic receptor subunits in M/O-dKO at both time points. To further investigate whether the differences can be attributed to a cell-autonomous function of Mct8/Oatp1c1 in distinct neurons, conditional mouse lines with a specific deletion of both TH transporters either in all GABAergic inhibitory interneurons (using Gad2-cre) or in all excitatory glutamatergic neurons (using Vglut2-cre) were generated and are currently analyzed. So far, no alterations in calretinin positive mossy cells were seen in both conditional knockout models indicating that mossy cell development is compromised by the TH deficient state in M/O-dKO mice. Altogether, our results point to an abnormal neuronal development in the hippocampus in the absence of Mct8 and Oatp1c1 that can disrupt the proper excitation/inhibition balance and thus impact seizure susceptibility.