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Cerebral Cortex Advance Access first published online on October 7, 2009
This version published online on October 28, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp212
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© 2009 The Authors
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Role of Late Maternal Thyroid Hormones in Cerebral Cortex Development: An Experimental Model for Human Prematurity

P. Berbel1, D. Navarro1, E. Ausó1, E. Varea1, A. E. Rodríguez1, J. J. Ballesta1, M. Salinas2, E. Flores2, C. C. Faura1 and G. Morreale de Escobar3,4

1 Instituto de Neurociencias, Universidad Miguel Hernández and Consejo Superior de Investigaciones Científicas, Sant Joan d’Alacant, 03550 Alicante, Spain, 2 Biochemistry Laboratory, Hospital Universitario Sant Joan, Sant Joan d'Alacant, 03550 Alicante, Spain Madrid, 3 Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain, 4 Center for Biomedical Research on Rare Diseases (CIBERER, U708), 28029 Madrid, Spain

Address correspondence to Pere Berbel, PhD, Instituto de Neurociencias, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Apartado de Correos 18, Sant Joan d'Alacant, 03550 Alicante, Spain. Email: pere.berbel{at}umh.es.

Hypothyroxinemia affects 35–50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers’ organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

Key Words: CREB signaling • hippocampal mossy fibers • premature birth • schizophrenia • short-term memory • subplate maturation • Timm's staining

Article has been update to correct author initial.


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