Increased seizure susceptibility in thyroid hormone transporter Mct8/Oatp1c1 knockout mice is associated with altered neurotransmitter systems development.

Abstract

Thyroid hormone (TH) transporters such as the monocarboxylate transporter Mct8 and the organic anion transporting protein Oatp1c1 facilitate TH transport into target cells. In humans, inactivating mutations in MCT8 result in Allan-Herndon-Dudley syndrome (AHDS), a severe psychomotor retardation with hallmarks of a central TH deficit and frequently observed seizures of unknown etiology. Here, we aimed to investigate seizure susceptibility in AHDS by using Mct8/Oatp1c1 double-knockout (Dko) mice, a well-established AHDS model. We tested seizure susceptibility using the pilocarpine model and observed a significantly faster occurrence of status epilepticus (SE) and more severe responses to seizure induction in Dko animals. We analyzed neuronal alterations in the hippocampus, an area central in seizure pathology, 12h after SE by immuno-fluorescence and in situ hybridization (ISH). Dko mice presented increased cFos immunoreactivity, and ectopic expression of somatostatin in CA3 neurons. To unravel underlying mechanisms, we studied neurotransmitter systems in murine hippocampi during development at P12 and in adulthood. Employing immuno-fluorescence, ISH and qPCR analyses, we revealed an abnormal development of the inhibitory GABAergic, excitatory glutamatergic and cholinergic systems in Dko mice. Together, our data point to an altered inhibition/excitation balance in the Dko hippocampus that may explain the increased seizure susceptibility.