Triac treatment prevents neurodevelopmental and locomotor impairments in thyroid hormone transporter Mct8/Oatp1c1 deficient mice

Abstract

Background Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to an insufficient TH transport and action in the CNS. As a therapeutic strategy, application of Triac (3, 5, 3`-triiodothyroacetic acid) and Ditpa (3, 5 -diiodo-thyropropionic acid) have been proposed as both thyromimetic compounds are not dependent on MCT8 for cellular entry. Here, we tested and directly compared the thyromimetic actions of Triac versus Ditpa in Mct8/Oatp1c1 double knockout mice (Dko), a suitable mouse model for human MCT8 deficiency. Methods: Newborn Dko mice were daily injected during the first three postnatal weeks with either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) and compared with Wt and Dko mice receiving saline injections. A second cohort of Dko mice was daily injected with Triac (400 ng/g) only between postnatal week 3 and 6. Thyromimetic effects in the CNS and peripheral tissues were monitored at different postnatal time points by immunofluorescence stainings for neural marker proteins, in situ hybridization and quantitative real time PCR. Locomotor performance was assessed in rotarod and hanging wire test. Acute brain slices of Triac treated Dko mice and their respective controls were used for electrophysiological recordings. Results: Only Dko mice injected with Triac (400 ng/g) during the first three postnatal weeks showed normalized myelination, differentiation of cortical GABAergic interneurons as well as locomotor performance. Electrophysiological recordings revealed an increased frequencies of cortical spontaneous miniature inhibitory postsynaptic currents in Dko mice and a normalization of this parameter in Triac treated Dko mice. In comparison, treatment of Dko mice with Ditpa at 4000 ng/g during the first three postnatal weeks resulted in normal myelination and cerebellar development but was less effective in restoring neuronal parameters and locomotor function. Finally, Triac was more potent than Ditpa in suppressing Trh and Tshb expression, respectively, and exerts stronger thyromimetic effects in liver and kidneys. Conclusions: In newborn Dko deficient mice, Triac is highly effective and more efficient than Ditpa in promoting CNS maturation and function. Yet, Triac treatment needs to be initiated directly after birth to achieve the most beneficial effects.

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

“…Thus, not surprisingly Mct8/Oatp1c1 DKO mice exhibit an altered composition of the cortical GABAergic interneuron network with a highly reduced number of parvalbumin expressing neurons in several regions of the cerebral cortex [ 6 , 42 ]. Furthermore, patch-clamp recordings of cortical neurons revealed an increased frequency of spontaneous miniature inhibitory postsynaptic currents in brain slices of Mct8/Oatp1c1 DKO mice confirming disturbed inhibitory neuronal activity in Mct8/Oatp1c1 deficiency [ 43 ]. Whether functional hyperconnectivity and impaired network function detected by rs-fMRI can be fully explained by an aberrant cortical GABAergic neurotransmission, remains to be further investigated particularly as an in-depth electrophysiological examination of the excitatory system is still missing.…”

“…As a prominent example for such a preclinical study, treatment of Mct8/Oatp1c1 DKO mice with the thyroid hormone analog TRIAC has been conducted in order to evaluate its potential in replacing TH during critical stages of brain development. When TRIAC treatment was initiated in newborn Mct8/Oatp1c1 DKO mice and continued during the first three postnatal weeks, normal myelination, undisturbed cerebellar development, and normal cortical GABAergic interneuron maturation could be achieved as shown by immunofluorescence analysis [ 10 , 43 ]. Moreover, this TRIAC treatment protocol was sufficient to restore locomotor performance and to achieve normal electrophysiological activity in cortical brain slices of Mct8/Oatp1c1 DKO mice [ 43 ].…”

“…When TRIAC treatment was initiated in newborn Mct8/Oatp1c1 DKO mice and continued during the first three postnatal weeks, normal myelination, undisturbed cerebellar development, and normal cortical GABAergic interneuron maturation could be achieved as shown by immunofluorescence analysis [ 10 , 43 ]. Moreover, this TRIAC treatment protocol was sufficient to restore locomotor performance and to achieve normal electrophysiological activity in cortical brain slices of Mct8/Oatp1c1 DKO mice [ 43 ]. Here, we followed the same TRIAC application protocol and could confirm an improved myelination in TRIAC treated Mct8/Oatp1c1 DKO animals by structural MRI.…”