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TRIAC treatment improves impaired brain network function and white matter loss in thyroid hormone transporter Mct8/Oatp1c1 deficient mice

Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout m...

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Main Authors: Reinwald, Jonathan Rochus (Author) , Weber-Fahr, Wolfgang (Author) , Cosa‐Linan, Alejandro (Author) , Becker, Robert (Author) , Sack, Markus (Author) , Falfán‐Melgoza, Claudia (Author) , Gass, Natalia (Author) , Braun, Urs (Author) , Clemm von Hohenberg, Christian (Author) , Chen, Jiesi (Author) , Mayerl, Steffen (Author) , Münte, Thomas Frank (Author) , Heuer, Heike (Author) , Sartorius, Alexander (Author)
Format: Article (Journal)
Language:English
Published: 8 December 2022
In: International journal of molecular sciences
Year: 2022, Volume: 23, Issue: 24, Pages: 1-19
ISSN:1422-0067
DOI:10.3390/ijms232415547
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/ijms232415547
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1422-0067/23/24/15547
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Author Notes:Jonathan Rochus Reinwald, Wolfgang Weber-Fahr, Alejandro Cosa-Linan, Robert Becker, Markus Sack, Claudia Falfan-Melgoza, Natalia Gass, Urs Braun, Christian Clemm von Hohenberg, Jiesi Chen, Steffen Mayerl, Thomas F. Muente, Heike Heuer and Alexander Sartorius
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Summary:Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout mice lacking MCT8 and organic anion transporting protein OATP1C1 (Mct8/Oatp1c1 DKO). In this study, we characterize impairments of brain structure and function in Mct8/Oatp1c1 DKO mice using multimodal magnetic resonance imaging (MRI) and assess the potential of the TH analogue 3,3′,5-triiodothyroacetic acid (TRIAC) to rescue this phenotype. Structural and functional MRI were performed in 11-weeks-old male Mct8/Oatp1c1 DKO mice (N = 10), wild type controls (N = 7) and Mct8/Oatp1c1 DKO mice (N = 13) that were injected with TRIAC (400 ng/g bw s.c.) daily during the first three postnatal weeks. Grey and white matter volume were broadly reduced in Mct8/Oatp1c1 DKO mice. TRIAC treatment could significantly improve white matter thinning but did not affect grey matter loss. Network-based statistic showed a wide-spread increase of functional connectivity, while graph analysis revealed an impairment of small-worldness and whole-brain segregation in Mct8/Oatp1c1 DKO mice. Both functional deficits could be substantially ameliorated by TRIAC treatment. Our study demonstrates prominent structural and functional brain alterations in Mct8/Oatp1c1 DKO mice that may underlie the psychomotor deficiencies in AHDS. Additionally, we provide preclinical evidence that early-life TRIAC treatment improves white matter loss and brain network dysfunctions associated with TH transporter deficiency.
Item Description:Gesehen am 14.02.2023
Physical Description:Online Resource
ISSN:1422-0067
DOI:10.3390/ijms232415547

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