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

Autor: Reinwald JR; Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.; Research Group Systems Neuroscience and Mental Health, Department of Psychiatry and Psychotherapy, University Medical Center Mainz, 55131 Mainz, Germany., Weber-Fahr W; Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany., Cosa-Linan A; Research Group in Silico Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany., Becker R; Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.; Center for Innovative Psychiatry and Psychotherapy Research, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany., Sack M; Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.; Center for Innovative Psychiatry and Psychotherapy Research, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany., Falfan-Melgoza C; Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany., Gass N; Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany., Braun U; Research Group Systems Neuroscience in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany., Clemm von Hohenberg C; Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany., Chen J; Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany., Mayerl S; Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany., Muente TF; Department of Neurology, University of Lübeck, 23538 Lübeck, Germany., Heuer H; Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.; Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany., Sartorius A; Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Dec 08; Vol. 23 (24). Date of Electronic Publication: 2022 Dec 08.
DOI: 10.3390/ijms232415547
Abstrakt: 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.
Databáze: MEDLINE
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