Developmental iodine deficiency resulting in hypothyroidism reduces hippocampal ERK1/2 and CREB in lactational and adolescent rats

Abstract

BackgroundDevelopmental iodine deficiency (ID) leads to inadequate thyroid hormone that impairs learning and memory with an unclear mechanism. Here, we show that hippocampal extracellular signal-regulated kinase (ERK1/2) and cAMP response element-binding protein (CREB) are implicated in the impaired learning and memory in lactational and adolescent rat hippocampus following developmental ID and hypothyroidism.MethodsThree developmental rat models were created by administrating dam rats with either iodine-deficient diet or propylthiouracil (PTU, 5 ppm or 15 ppm)-added drinking water from gestational day (GD) 6 till postnatal day (PN) 28. Then, the total and phorsporylated ERK1/2 and total and phorsporylated CREB in the hippocampus were detected with western blot on PN14, PN21, PN28 and PN42.ResultsThe iodine-deficient and hypothyroid pups showed lower serum FT3 and FT4 levels, smaller body size, and delayed eyes opening. The mean number of surviving cells in the hippocampus of the iodine-deficient and 15 ppm PTU-treated rats was significantly reduced compared to controls (P < 0.05). Iodine-deficient and 15 ppm PTU-treatment groups demonstrated significantly lower level of total and phosphorylated ERK1/2 and CREB than the controls on PN14, PN21 and PN28 (P < 0.05, respectively). The reduction of ERK1/2 and CREB was not reversible with the restoration of serum thyroid hormone concentrations on PN42.ConclusionsDevelopmental ID and hypothyroidism down-regulate hippocampal ERK1/2 and CREB in lactational and adolescent rats.

Hypothyroidism following developmental iodine deficiency reduces hippocampal neurogranin, CaMK II and calmodulin and elevates calcineurin in lactational rats

“…Our previous studies confirmed the impairment of brain development following developmental ID and hypothyroidism (Dong et al, 2005(Dong et al, , 2009aGong et al, 2010). The present study has further shown that, in the lactational pups, developmental ID and hypothyroidism induced reduction of neurogranin, CaMKII and CaM and elevation of CaN in hippocampal CA1 and CA3 regions.…”

“…Our study shows that developmental ID and hypothyroidism (15 ppm PTU) significantly decreased serum FT 3 and FT 4 in pups (Dong et al, 2009a), significantly reduced neurogranin, CaMKII and CaM, and significantly increased CaN in hippocampal CA1 and CA3 regions in the lactational rats. Given that RC3 is the only development-related gene regulated by thyroid hormone, adult hypothyroidism reversibly decreases neurogranin expression in hippocampus Vallortigara et al, 2008).…”

“…Compared with the control groups, the weights of pups in the treatment groups were reduced by 26–61% on PN14, and 36–68% on PN21, respectively. On PN14 and PN21, the serum FT 3 and FT 4 concentrations in the iodine‐deficient and 15 ppm treatment groups were significantly lower than those of the controls ( P < 0.05) (Dong et al, 2009a).…”

Iodine deficiency increases apoptosis and decreases synaptotagmin-1 and PSD-95 in rat hippocampus

“…[28][29][30][31] And it affects the brain development might be due to the decrease of surviving neuron that can perform normal function, and to a lower expression of the functional genes in each neuron. 29,31 The present study has further demonstrated that developmental ID and PTU treatment induced the increase of apoptotic cells, extension of apoptotic process, and the decrease of synaptotagmin-1 and PSD-95 in the hippocampus, which might be ascribed to ID-induced impairment of brain development. …”

“…In previous experiments, we had obtained iodine-deficient and 15 ppm PTU-treatment rat. 31 Comparing with the control groups, the weights and the serum free triiodothyronine (FT 3 ) and free thyroxine (FT 4 ) concentrations of pups in the iodinedeficient and 15 ppm PTU-treatment groups were significantly reduced (P < 0.05). Prior to the sacrifice on PND14, PND21, and PND28, the same number of pups were randomly taken from different litters with a similar sex ratio in each group.…”