Endocrine Abstracts

In humans, inactivating mutations in the thyroid hormone transporter MCT8 result in a severe psychomotor retardation characterized by neurological impairments and frequent epileptic seizures of unknown etiology that are thought to derive from a reduced transport of TH across brain barriers and into neural cells. Here, we aimed to investigate the mechanisms underlying the seizure susceptibility in MCT8 deficiency by using Mct8/Oatp1c1 double knockout (dKO) mice, a well-established mouse model for this pathology. We first assessed seizure susceptibility in dKO mice by subjecting the animals to the convulsant agent pilocarpine and found a highly reduced seizure threshold and a stronger response to seizure induction in TH transporter deficient mice. Analysis of the brains 12h after seizure induction revealed a strong expression of the neuronal activation marker cFos together with increased somatostatin transcript and protein levels in hippocampi of dKO animals. To unravel possible alterations underlying the differential seizure response, we studied the expression pattern of inhibitory and excitatory neuronal components by immunofluorescence, in situ hybridization and qPCR during early postnatal development (P12) and in adulthood (P120). Our analysis revealed an abnormal development of the inhibitory GABAergic as well as the excitatory glutamatergic and cholinergic systems in the hippocampus of dKO animals. Increased expression levels of glutamate receptor subunits (such as NMDA receptor subunits Nr1 and GluN2b) and cholinergic metabotropic receptors were observed in adult dKO mice. Alterations in neurotransmitter systems could be further confirmed by LC-MS/MS analysis using hippocampal homogenates of adult control and dKO mice that revealed a decrease in proteins involved in ion homeostasis and neuronal activity (such as Kir4.1 and Atp2b2) in dKO hippocampi. Altogether, our results point to an aberrant development of different neurotransmitter systems in the absence of TH transporters Mct8/Oatp1c1 that leads to an imbalance excitatory versus inhibitory neuronal signaling that ultimately culminates in increased seizure susceptibility.