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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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Autores principales: Reinwald, Jonathan Rochus, Weber-Fahr, Wolfgang, Cosa-Linan, Alejandro, Becker, Robert, Sack, Markus, Falfan-Melgoza, Claudia, Gass, Natalia, Braun, Urs, Clemm von Hohenberg, Christian, Chen, Jiesi, Mayerl, Steffen, Muente, Thomas F., Heuer, Heike, Sartorius, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779161/
https://www.ncbi.nlm.nih.gov/pubmed/36555189
http://dx.doi.org/10.3390/ijms232415547
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author Reinwald, Jonathan Rochus
Weber-Fahr, Wolfgang
Cosa-Linan, Alejandro
Becker, Robert
Sack, Markus
Falfan-Melgoza, Claudia
Gass, Natalia
Braun, Urs
Clemm von Hohenberg, Christian
Chen, Jiesi
Mayerl, Steffen
Muente, Thomas F.
Heuer, Heike
Sartorius, Alexander
author_facet Reinwald, Jonathan Rochus
Weber-Fahr, Wolfgang
Cosa-Linan, Alejandro
Becker, Robert
Sack, Markus
Falfan-Melgoza, Claudia
Gass, Natalia
Braun, Urs
Clemm von Hohenberg, Christian
Chen, Jiesi
Mayerl, Steffen
Muente, Thomas F.
Heuer, Heike
Sartorius, Alexander
author_sort Reinwald, Jonathan Rochus
collection PubMed
description 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.
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spelling pubmed-97791612022-12-23 TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice Reinwald, Jonathan Rochus Weber-Fahr, Wolfgang Cosa-Linan, Alejandro Becker, Robert Sack, Markus Falfan-Melgoza, Claudia Gass, Natalia Braun, Urs Clemm von Hohenberg, Christian Chen, Jiesi Mayerl, Steffen Muente, Thomas F. Heuer, Heike Sartorius, Alexander Int J Mol Sci Article 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. MDPI 2022-12-08 /pmc/articles/PMC9779161/ /pubmed/36555189 http://dx.doi.org/10.3390/ijms232415547 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Reinwald, Jonathan Rochus
Weber-Fahr, Wolfgang
Cosa-Linan, Alejandro
Becker, Robert
Sack, Markus
Falfan-Melgoza, Claudia
Gass, Natalia
Braun, Urs
Clemm von Hohenberg, Christian
Chen, Jiesi
Mayerl, Steffen
Muente, Thomas F.
Heuer, Heike
Sartorius, Alexander
TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice
title TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice
title_full TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice
title_fullStr TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice
title_full_unstemmed TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice
title_short TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice
title_sort triac treatment improves impaired brain network function and white matter loss in thyroid hormone transporter mct8/oatp1c1 deficient mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779161/
https://www.ncbi.nlm.nih.gov/pubmed/36555189
http://dx.doi.org/10.3390/ijms232415547
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