Neuronal 3′,3,5-Triiodothyronine (T3) Uptake and Behavioral Phenotype of Mice Deficient inMct8, the Neuronal T3Transporter Mutated in Allan–Herndon–Dudley Syndrome
| العنوان: | Neuronal 3′,3,5-Triiodothyronine (T3) Uptake and Behavioral Phenotype of Mice Deficient inMct8, the Neuronal T3Transporter Mutated in Allan–Herndon–Dudley Syndrome |
|---|---|
| المؤلفون: | Thomas Klopstock, Andreas Zimmer, Ulrich Schweizer, Helmut Fuchs, Cristiane Blechschmidt, Josef Köhrle, Valerie Gailus-Durner, Lore Becker, Annette Grüters, Wolfgang Wurst, Ildiko Racz, Stephan Roth, Anja U. Bräuer, Sabine M. Hölter, Thomas Naumann, Eva K. Wirth, Martin Hrabé de Angelis |
| المصدر: | The Journal of Neuroscience. 29:9439-9449 |
| بيانات النشر: | Society for Neuroscience, 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Monocarboxylic Acid Transporters, medicine.medical_specialty, Amino Acid Transport System y+, Neuropsychological Tests, Hyperthyroidism, Mice, Hypothyroidism, Internal medicine, medicine, Animals, Humans, RNA, Messenger, Cells, Cultured, Thyroid hormone transport, Mice, Knockout, Neurons, Monocarboxylate transporter, Allan–Herndon–Dudley syndrome, Triiodothyronine, Behavior, Animal, Symporters, biology, Fusion Regulatory Protein 1, Light Chains, General Neuroscience, Brain, Membrane Transport Proteins, Transporter, Syndrome, Articles, Human brain, medicine.disease, Phenotype, medicine.anatomical_structure, Endocrinology, Symporter, Mental Retardation, X-Linked, biology.protein, Microglia, Hormone |
| الوصف: | Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan–Herndon–Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3′,3,5-triiodothyronine (T3) plasma levels. Mice deficient inMct8replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lackingMct8. Therefore, we subjectedMct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent onMct8are in a hypothyroid state, whereas neurons expressing other T3transporters become hyperthyroid, if they are exposed directly to the high plasma T3. The majority of T3uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T3transporter classes. mRNAs encoding six T3transporters, including L-type amino acid transporters (LATs), were coexpressed withMct8in isolated neurons. We then demonstratedLat2expression in cultured neurons and throughout murine brain development. In contrast,LAT2is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype inMCT8-deficient patients, whereasMct8-deficient mouse neurons are functionally complemented by other transporters, for possiblyLat2. |
| تدمد: | 1529-2401 0270-6474 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f883c89e2a4fd917078ccfb93361ec6Test https://doi.org/10.1523/jneurosci.6055-08.2009Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3f883c89e2a4fd917078ccfb93361ec6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15292401 02706474 |
|---|