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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

Histogram showing step-down latencies in seconds at 1, 3, and 24 h after the initial footshock in control and LMH pups at P39. Pups from LMH dams show a 24.9% reduction in the step-down latency at 1 h after the footshock. Error bars represent ± standard deviation; n.s., no significant differences; *P <0.001 for LMH compared with control group (n = 23 for control and n = 8 for LMH group).
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fig11: Histogram showing step-down latencies in seconds at 1, 3, and 24 h after the initial footshock in control and LMH pups at P39. Pups from LMH dams show a 24.9% reduction in the step-down latency at 1 h after the footshock. Error bars represent ± standard deviation; n.s., no significant differences; *P <0.001 for LMH compared with control group (n = 23 for control and n = 8 for LMH group).

Mentions: Step-down latencies were statistically lower (P < 0.001) in LMH (118.6 ± 19.4 s) than in C pups (158 ± 11.51 s) in the 1-h test session. The number of animals that did not step down in the ceiling period was lower (P < 0.001) in the LMH (one of eight) than in the C group (19 of 23), also in the 1-h test. No differences were found between the 3- and 24-h test sessions (Fig. 11). In addition, pCREB/pATF1, pCREB/CREB, pERK1/ERK2, and pERK2/ERK2 ratios in the hippocampus were reduced in LMH compared with C pups (59.1%, 66.7%, 44.4%, and 42.9%, respectively; P < 0.001; Fig. 12). These data indicate an altered memory consolidation in LMH pups.


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)

Histogram showing step-down latencies in seconds at 1, 3, and 24 h after the initial footshock in control and LMH pups at P39. Pups from LMH dams show a 24.9% reduction in the step-down latency at 1 h after the footshock. Error bars represent ± standard deviation; n.s., no significant differences; *P <0.001 for LMH compared with control group (n = 23 for control and n = 8 for LMH group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig11: Histogram showing step-down latencies in seconds at 1, 3, and 24 h after the initial footshock in control and LMH pups at P39. Pups from LMH dams show a 24.9% reduction in the step-down latency at 1 h after the footshock. Error bars represent ± standard deviation; n.s., no significant differences; *P <0.001 for LMH compared with control group (n = 23 for control and n = 8 for LMH group).
Mentions: Step-down latencies were statistically lower (P < 0.001) in LMH (118.6 ± 19.4 s) than in C pups (158 ± 11.51 s) in the 1-h test session. The number of animals that did not step down in the ceiling period was lower (P < 0.001) in the LMH (one of eight) than in the C group (19 of 23), also in the 1-h test. No differences were found between the 3- and 24-h test sessions (Fig. 11). In addition, pCREB/pATF1, pCREB/CREB, pERK1/ERK2, and pERK2/ERK2 ratios in the hippocampus were reduced in LMH compared with C pups (59.1%, 66.7%, 44.4%, and 42.9%, respectively; P < 0.001; Fig. 12). These data indicate an altered memory consolidation in LMH pups.

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