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Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity.

Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM - Cereb. Cortex (2009)

Bottom Line: At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus.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.In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Neurociencias, Universidad Miguel Hernández and Consejo Superior de Investigaciones Científicas, Sant Joan d'Alacant, Alicante, Spain. pere.berbel@umh.es

ABSTRACT
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.

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Related in: MedlinePlus

Photomicrographs of coronal sections of the hippocampus showing ZnT-3 labeling in control (A) and LMH (B) pups at P40. A decreased intensity of the immunolabeling can be observed in the stratum oriens (arrowhead) in LMH pups compared with controls. DG, dentate gyrus.
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fig10: Photomicrographs of coronal sections of the hippocampus showing ZnT-3 labeling in control (A) and LMH (B) pups at P40. A decreased intensity of the immunolabeling can be observed in the stratum oriens (arrowhead) in LMH pups compared with controls. DG, dentate gyrus.

Mentions: Zn-positive areas were observed in the cortex and hippocampal formation of C and LMH pups at P40, which coincided with previous descriptions for normal rats (Gaarskjaer 1978). As in C rats, Zn-positive areas were observed in the stratum moleculare of the dentate gyrus, the hilus of CA4, and the strata radiatum and oriens of CA3, CA2, and CA1, with increased labeling in the hilus of CA4 and in 2 bands adjacent to the pyramidal cell layer of CA3 located in the strata radiatum and oriens (Fig. 9A–C). However, at P40, the Zn-positive labeled area in the stratum oriens was reduced by 41.5% in LMH pups (36 464.6 ± 7972.8 μm2) compared with C pups (64 817.7 ± 9827.0 μm2; P < 0.05; Fig. 7D–F). ZnT-3 immunolabeling at P40 confirmed these findings, the immunolabeling in the stratum oriens of CA3 in LMH pups being much weaker than in C pups (Fig. 10A,B, arrowheads).


Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity.

Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM - Cereb. Cortex (2009)

Photomicrographs of coronal sections of the hippocampus showing ZnT-3 labeling in control (A) and LMH (B) pups at P40. A decreased intensity of the immunolabeling can be observed in the stratum oriens (arrowhead) in LMH pups compared with controls. DG, dentate gyrus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2871377&req=5

fig10: Photomicrographs of coronal sections of the hippocampus showing ZnT-3 labeling in control (A) and LMH (B) pups at P40. A decreased intensity of the immunolabeling can be observed in the stratum oriens (arrowhead) in LMH pups compared with controls. DG, dentate gyrus.
Mentions: Zn-positive areas were observed in the cortex and hippocampal formation of C and LMH pups at P40, which coincided with previous descriptions for normal rats (Gaarskjaer 1978). As in C rats, Zn-positive areas were observed in the stratum moleculare of the dentate gyrus, the hilus of CA4, and the strata radiatum and oriens of CA3, CA2, and CA1, with increased labeling in the hilus of CA4 and in 2 bands adjacent to the pyramidal cell layer of CA3 located in the strata radiatum and oriens (Fig. 9A–C). However, at P40, the Zn-positive labeled area in the stratum oriens was reduced by 41.5% in LMH pups (36 464.6 ± 7972.8 μm2) compared with C pups (64 817.7 ± 9827.0 μm2; P < 0.05; Fig. 7D–F). ZnT-3 immunolabeling at P40 confirmed these findings, the immunolabeling in the stratum oriens of CA3 in LMH pups being much weaker than in C pups (Fig. 10A,B, arrowheads).

Bottom Line: At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus.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.In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Neurociencias, Universidad Miguel Hernández and Consejo Superior de Investigaciones Científicas, Sant Joan d'Alacant, Alicante, Spain. pere.berbel@umh.es

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus