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

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.

Sciatic nerve analysis in thyroid hormone transporters Mct8 and Oatp1c1 knockout mice.

Objective: Mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) cause Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with muscle hypoplasia and spastic paraplegia as key symptoms. These abnormalities have been attributed to impaired TH transport across brain barriers and into neural cells, thereby affecting brain development and function. Likewise, Mct8/Oatp1c1 (organic anion-transporting polypeptide 1c1) double knockout (M/Odko) mice, a well-established murine AHDS model, display a strongly reduced TH passage into the brain as well as locomotor abnormalities.

Local Thyroid Hormone Action in Brain Development.

Proper brain development essentially depends on the timed availability of sufficient amounts of thyroid hormone (TH). This, in turn, necessitates a tightly regulated expression of TH signaling components such as TH transporters, deiodinases, and TH receptors in a brain region- and cell-specific manner from early developmental stages onwards. Abnormal TH levels during critical stages, as well as mutations in TH signaling components that alter the global and/or local thyroidal state, result in detrimental consequences for brain development and neurological functions that involve alterations in central neurotransmitter systems.

Distinct Actions of the Thyroid Hormone Transporters Mct8 and Oatp1c1 in Murine Adult Hippocampal Neurogenesis.

Inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in Allan-Herndon-Dudley Syndrome, a severe form of psychomotor retardation, while inactivating mutations in another TH transporter, organic anion transporting polypeptide 1c1 (OATP1C1), are linked to juvenile neurodegeneration. These diseases point to essential roles for TH transporters in CNS function. We recently defined the presence of Mct8 in adult hippocampal progenitors and mature granule cell neurons and unraveled cell-autonomous and indirect requirements for Mct8 in adult hippocampal neurogenesis.