碘缺乏和甲状腺功能减退对大鼠仔鼠小脑发育的损伤及CaMKⅡ、CaM和CaN表达影响的研究
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摘要
目的
本研究分别通过碘缺乏饲料及PTU饮水建立甲状腺功能减退大鼠模型,观察碘缺乏及甲状腺功能减退大鼠仔鼠小脑发育的影响,以及对CaMKⅡ、CaM、CaN表达的影响。为阐明碘缺乏及甲状腺功能减退损害小脑神经发育,导致小脑功能障碍的机制提供实验依据。
方法
健康2月龄雌性Wistar大鼠,交配妊娠后,取孕鼠28只按体重随机分成对照组、甲状腺功能减退-1组(5ppmPTU组)、甲状腺功能减退-2组(15ppmPTU组)和碘缺乏组,每组7只雌鼠。自妊娠第6日起,对照组继续饲以普通饲料,饮用自来水;甲状腺功能减退-1组给予5ppmPTU丙基硫尿嘧啶(propylthiouracil,PTU)饮水;甲状腺功能减退-2组给予15ppmPTU丙基硫尿嘧啶饮水,饲以普通饲料;碘缺乏组饲以缺碘地区粮食配制的饲料,饮用自来水,直至仔鼠出生后第28天(PN28)。PN7、PN14、PN21、PN28、PN42取仔鼠称重;固相化学免疫发光法测定血清中FT3、FT4;取小脑称重;取小脑皮质进行尼氏染色及相关蛋白免疫组化染色。
结果
1.碘缺乏和甲状腺功能减退对母鼠和仔鼠体重及仔鼠小脑脑重、开眼率结果的影响。
孕期和哺乳期碘缺乏组母鼠体重明显低于对照组(P＜0.05);5ppmPTU组、15ppmPTU组和碘缺乏组仔鼠体重增长缓慢,小脑脑重减轻,均显著低于正常水平(P＜0.05)。15ppmPTU组和碘缺乏组仔鼠开眼延迟,同期开眼率明显低于对照组(P＜0.05)。
2.碘缺乏和甲状腺功能减退能够影响大鼠仔鼠小脑神经发育。
PN7时,各组大鼠仔鼠小脑神经元的尼氏小体的平均积分光密度值无统计学意义。PN14、PN21、PN28和PN42时,5ppmPTU组、15ppmPTU组和碘缺乏组仔鼠小脑神经元的尼氏小体的平均积分光密度值均显著低于对照组,具有统计学意义(P＜0.05)。PN21时,碘缺乏组亦显著低于5ppmPTU组,具有统计学意义(P＜0.05)。
3.碘缺乏和甲状腺功能减退对仔鼠小脑皮质CaMKⅡ表达的影响。
PN7、PN14、PN21、PN28时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaMKⅡ表达均显著低于对照组和5ppmPTU组,具有统计学意义(P＜0.05)。PN42时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaMKⅡ表达显著低于对照组,具有统计学意义(P＜0.05)。
4.碘缺乏和甲状腺功能减退对仔鼠小脑皮质CaM表达的影响。
PN7时,碘缺乏组仔鼠小脑皮质CaM表达显著低于对照组,具有统计学意义(P＜0.05)。PN14时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaM表达显著低于对照组和5ppmPTU组,具有统计学意义(P＜0.05)。PN21时,5ppmPTU组、15ppmPTU组和碘缺乏组仔鼠小脑皮质CaM表达显著低于对照组,15ppmPTU组和碘缺乏组亦显著低于5ppmPTU组,具有统计学意义(P＜0.05)。PN28和PN42时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaM表达显著低于对照组和5ppmPTU组,碘缺乏组亦显著低于15ppmPTU组,具有统计学意义(P＜0.05)。
5.碘缺乏和甲状腺功能减退对仔鼠小脑皮质CaN表达的影响。
PN7时,各组仔鼠小脑皮质CaN表达均无显著差异。PN14时,碘缺乏组仔鼠小脑皮质CaN表达显著高于对照组,具有统计学意义(P＜0.05)。PN21时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaN表达显著高于对照组,具有统计学意义(P＜0.05)。PN28时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaN表达显著高于对照组,碘缺乏组亦显著高于5ppmPTU组,具有统计学意义(P＜0.05)。PN42时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaN表达显著高于对照组,具有统计学意义(P＜0.05)。
结论
1、碘缺乏和甲状腺功能减退可影响大鼠仔鼠发育,使其体重下降,小脑脑重减轻,开眼延迟。
2、碘缺乏和甲状腺功能减退能够影响大鼠仔鼠小脑神经发育。
3、碘缺乏和甲状腺功能减退能够降低大鼠仔鼠小脑CaMKⅡ、CaM的表达,提高CaN的表达。
总之,碘缺乏和甲状腺功能减退可影响大鼠仔鼠小脑相关蛋白的表达,从而损害仔鼠小脑,导致脑神经发育障碍。
Objective
Through gestation and lactation,iodine deficient or hypothyroid dam rats were administered either an iodine-deficient diet or PTU-added drinking water.We have tested whether congenital iodine deficiency and hypothyroidism could regulate expression of CaMKⅡ,CAM,CaN in pup Cerebellum cortex.To figure out the mechanism that iodine deficiency and hypothyroidism impair functional lesion in pup Cerebellum.
Methods
Female Wistar rats(n=28) aging 2 after pregnancy were randomly divided into four groups:control group,iodine deficient group,hypothyroid-1 group(5ppmPTU) and hypothyroid-2 group(15ppmPTU).The control group was fed a normal diet and tap water during the experiment.The iodine deficient group was fed an iodine-deficient 6diet and tap-water.The hypothyroid-1 group was fed a normal diet and had 5ppm PTU-added water and the hypothyroid-2 group had 15ppm PTU-added water.All the groups were from GD6 through to postnatal day(PN) 28.On PN7,PN14,PN21,PN28, pups in each group were weighed and blood samples were taken for the FT_3,FT_4 super-sensitive chemiluminescence immunoassay.The part of the cerebellum was separated from the brain for protein detection by Nissl's staining and immunohistochemistry.
Results
1、Effects of iodine deficiency and hypothyroidism on Weights of dam and weights of cerebellum,pup and eye opening.
In all three groups of dam rats,dams from iodine-deficient groups were significantly lighter than controls in pregnancy and gestation(P<0.05).Weights of pup and weights of cerebellum from iodine-deficient and 15ppmPTU groups were significantly smaller than controls(P<0.05).Eye opening was delayed in iodine-deficient and 15ppmPTU treatment groups,and the ratio of pups within a litter with both eyes opening was lower than controls in the same time.
2、Effects of iodine deficiency and hypothyroidism on cerebellar neural development of pup rats.
In the result of Nissl's staining:On PN7,there were no significantly difference in all the groups.On PN14,PN21,PN28 and PN42,Nissl's body expression in 5ppmPTU, 15ppmPTU and iodine-deficient groups were significantly lower than those of controls (P<0.05).On PN21,Nissl's body expression in iodine-deficient groups were significantly lower than those of 5ppmPTU groups(P<0.05).
3、Effects of iodine deficiency and hypothyroidism on CaMKⅡexpression in cerebellar cortex of pup rats.
In the result of immunohistochemistry:On PN7,PN 14,PN21 and PN28,CaMKⅡexpression in 15ppmPTU and iodine-deficient groups were significantly lower than those of controls and 5ppmPTU(P<0.05).On PN42,CaMKⅡexpression in 15ppmPTU and iodine-deficient groups were significantly lower than those of control groups(P<0.05).
4、Effects of iodine deficiency and hypothyroidism on CaM expression in cerebellar cortex of pup rats.
In the result of immunohistochemistry:On PN7,CaM expression in iodine-deficient groups were significantly lower than those of controls(P<0.05),on PN14,CaM expression in 15ppmPTU and iodine-deficient groups were significantly lower than those of controls and 5ppmPTU groups(P＜0.05).On PN21,CaM expression in 5ppmPTU,15ppmPTU and iodine-deficient groups were significantly lower than those of controls(P＜0.05),CaM expression in 15ppmPTU and iodine-deficient groups were significantly lower than those of 5ppmPTU group (P＜0.05).On PN28 and PN42,CaM expression in 15ppmPTU and iodine-deficient groups were significantly lower than those of controls and 5ppmPTU group(P＜0.05), CaM expression in iodine-deficient groups were significantly lower than those of 15ppmPTU group(P＜0.05).
5、Effects of iodine deficiency and hypothyroidism on CaN expression in cerebellar cortex of pup rats.
In the result of immunohistochemistry:On PN7,there were no significantly difference in all the groups.On PN14,CaN expression in iodine-deficient groups were significantly higher than those of controls(P＜0.05).On PN21,CaN expression in 15ppmPTU and iodine-deficient groups were significantly higher than those of controls (P＜0.05).On PN28,CaN expression in 15ppmPTU and iodine-deficient groups were significantly higher than those of controls(P＜0.05),CaN expression in iodine-deficient groups were significantly higher than those of 5ppmPTU group(P＜0.05).On PN42, CaN expression in 15ppmPTU and iodine-deficient groups were significantly higher than those of controls(P＜0.05).
Conclusion
1、Iodine deficiency and hypothyroidism may effect pups development and lead to the body weights decrease and eye opening delay.
2、Iodine deficiency and hypothyroidism change cerebellar nerves development.
3、Iodine deficiency and hypothyroidism may reduce the expression of CaMKⅡ, CaM,and increase the expression of CaN in pup cerebellar cortex.
In summary,our results demonstrate that transient exposure to a period of iodine deficiency and hypothyroidism during a period of brain development changed cerebellar morphology and effected the expression of CaMKⅡ,CaM,and CaN.The changes are likely to impaired synaptic plasticity,effected the formation of normal neural circuit,and resulted in cerebellar development disturbance.
本研究分别通过碘缺乏饲料及PTU饮水建立甲状腺功能减退大鼠模型,观察碘缺乏及甲状腺功能减退大鼠仔鼠小脑发育的影响,以及对CaMKⅡ、CaM、CaN表达的影响。为阐明碘缺乏及甲状腺功能减退损害小脑神经发育,导致小脑功能障碍的机制提供实验依据。
方法
健康2月龄雌性Wistar大鼠,交配妊娠后,取孕鼠28只按体重随机分成对照组、甲状腺功能减退-1组(5ppmPTU组)、甲状腺功能减退-2组(15ppmPTU组)和碘缺乏组,每组7只雌鼠。自妊娠第6日起,对照组继续饲以普通饲料,饮用自来水;甲状腺功能减退-1组给予5ppmPTU丙基硫尿嘧啶(propylthiouracil,PTU)饮水;甲状腺功能减退-2组给予15ppmPTU丙基硫尿嘧啶饮水,饲以普通饲料;碘缺乏组饲以缺碘地区粮食配制的饲料,饮用自来水,直至仔鼠出生后第28天(PN28)。PN7、PN14、PN21、PN28、PN42取仔鼠称重;固相化学免疫发光法测定血清中FT3、FT4;取小脑称重;取小脑皮质进行尼氏染色及相关蛋白免疫组化染色。
结果
1.碘缺乏和甲状腺功能减退对母鼠和仔鼠体重及仔鼠小脑脑重、开眼率结果的影响。
孕期和哺乳期碘缺乏组母鼠体重明显低于对照组(P＜0.05);5ppmPTU组、15ppmPTU组和碘缺乏组仔鼠体重增长缓慢,小脑脑重减轻,均显著低于正常水平(P＜0.05)。15ppmPTU组和碘缺乏组仔鼠开眼延迟,同期开眼率明显低于对照组(P＜0.05)。
2.碘缺乏和甲状腺功能减退能够影响大鼠仔鼠小脑神经发育。
PN7时,各组大鼠仔鼠小脑神经元的尼氏小体的平均积分光密度值无统计学意义。PN14、PN21、PN28和PN42时,5ppmPTU组、15ppmPTU组和碘缺乏组仔鼠小脑神经元的尼氏小体的平均积分光密度值均显著低于对照组,具有统计学意义(P＜0.05)。PN21时,碘缺乏组亦显著低于5ppmPTU组,具有统计学意义(P＜0.05)。
3.碘缺乏和甲状腺功能减退对仔鼠小脑皮质CaMKⅡ表达的影响。
PN7、PN14、PN21、PN28时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaMKⅡ表达均显著低于对照组和5ppmPTU组,具有统计学意义(P＜0.05)。PN42时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaMKⅡ表达显著低于对照组,具有统计学意义(P＜0.05)。
4.碘缺乏和甲状腺功能减退对仔鼠小脑皮质CaM表达的影响。
PN7时,碘缺乏组仔鼠小脑皮质CaM表达显著低于对照组,具有统计学意义(P＜0.05)。PN14时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaM表达显著低于对照组和5ppmPTU组,具有统计学意义(P＜0.05)。PN21时,5ppmPTU组、15ppmPTU组和碘缺乏组仔鼠小脑皮质CaM表达显著低于对照组,15ppmPTU组和碘缺乏组亦显著低于5ppmPTU组,具有统计学意义(P＜0.05)。PN28和PN42时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaM表达显著低于对照组和5ppmPTU组,碘缺乏组亦显著低于15ppmPTU组,具有统计学意义(P＜0.05)。
5.碘缺乏和甲状腺功能减退对仔鼠小脑皮质CaN表达的影响。
PN7时,各组仔鼠小脑皮质CaN表达均无显著差异。PN14时,碘缺乏组仔鼠小脑皮质CaN表达显著高于对照组,具有统计学意义(P＜0.05)。PN21时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaN表达显著高于对照组,具有统计学意义(P＜0.05)。PN28时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaN表达显著高于对照组,碘缺乏组亦显著高于5ppmPTU组,具有统计学意义(P＜0.05)。PN42时,15ppmPTU组和碘缺乏组仔鼠小脑皮质CaN表达显著高于对照组,具有统计学意义(P＜0.05)。
结论
1、碘缺乏和甲状腺功能减退可影响大鼠仔鼠发育,使其体重下降,小脑脑重减轻,开眼延迟。
2、碘缺乏和甲状腺功能减退能够影响大鼠仔鼠小脑神经发育。
3、碘缺乏和甲状腺功能减退能够降低大鼠仔鼠小脑CaMKⅡ、CaM的表达,提高CaN的表达。
总之,碘缺乏和甲状腺功能减退可影响大鼠仔鼠小脑相关蛋白的表达,从而损害仔鼠小脑,导致脑神经发育障碍。
Objective
Through gestation and lactation,iodine deficient or hypothyroid dam rats were administered either an iodine-deficient diet or PTU-added drinking water.We have tested whether congenital iodine deficiency and hypothyroidism could regulate expression of CaMKⅡ,CAM,CaN in pup Cerebellum cortex.To figure out the mechanism that iodine deficiency and hypothyroidism impair functional lesion in pup Cerebellum.
Methods
Female Wistar rats(n=28) aging 2 after pregnancy were randomly divided into four groups:control group,iodine deficient group,hypothyroid-1 group(5ppmPTU) and hypothyroid-2 group(15ppmPTU).The control group was fed a normal diet and tap water during the experiment.The iodine deficient group was fed an iodine-deficient 6diet and tap-water.The hypothyroid-1 group was fed a normal diet and had 5ppm PTU-added water and the hypothyroid-2 group had 15ppm PTU-added water.All the groups were from GD6 through to postnatal day(PN) 28.On PN7,PN14,PN21,PN28, pups in each group were weighed and blood samples were taken for the FT_3,FT_4 super-sensitive chemiluminescence immunoassay.The part of the cerebellum was separated from the brain for protein detection by Nissl's staining and immunohistochemistry.
Results
1、Effects of iodine deficiency and hypothyroidism on Weights of dam and weights of cerebellum,pup and eye opening.
In all three groups of dam rats,dams from iodine-deficient groups were significantly lighter than controls in pregnancy and gestation(P<0.05).Weights of pup and weights of cerebellum from iodine-deficient and 15ppmPTU groups were significantly smaller than controls(P<0.05).Eye opening was delayed in iodine-deficient and 15ppmPTU treatment groups,and the ratio of pups within a litter with both eyes opening was lower than controls in the same time.
2、Effects of iodine deficiency and hypothyroidism on cerebellar neural development of pup rats.
In the result of Nissl's staining:On PN7,there were no significantly difference in all the groups.On PN14,PN21,PN28 and PN42,Nissl's body expression in 5ppmPTU, 15ppmPTU and iodine-deficient groups were significantly lower than those of controls (P<0.05).On PN21,Nissl's body expression in iodine-deficient groups were significantly lower than those of 5ppmPTU groups(P<0.05).
3、Effects of iodine deficiency and hypothyroidism on CaMKⅡexpression in cerebellar cortex of pup rats.
In the result of immunohistochemistry:On PN7,PN 14,PN21 and PN28,CaMKⅡexpression in 15ppmPTU and iodine-deficient groups were significantly lower than those of controls and 5ppmPTU(P<0.05).On PN42,CaMKⅡexpression in 15ppmPTU and iodine-deficient groups were significantly lower than those of control groups(P<0.05).
4、Effects of iodine deficiency and hypothyroidism on CaM expression in cerebellar cortex of pup rats.
In the result of immunohistochemistry:On PN7,CaM expression in iodine-deficient groups were significantly lower than those of controls(P<0.05),on PN14,CaM expression in 15ppmPTU and iodine-deficient groups were significantly lower than those of controls and 5ppmPTU groups(P＜0.05).On PN21,CaM expression in 5ppmPTU,15ppmPTU and iodine-deficient groups were significantly lower than those of controls(P＜0.05),CaM expression in 15ppmPTU and iodine-deficient groups were significantly lower than those of 5ppmPTU group (P＜0.05).On PN28 and PN42,CaM expression in 15ppmPTU and iodine-deficient groups were significantly lower than those of controls and 5ppmPTU group(P＜0.05), CaM expression in iodine-deficient groups were significantly lower than those of 15ppmPTU group(P＜0.05).
5、Effects of iodine deficiency and hypothyroidism on CaN expression in cerebellar cortex of pup rats.
In the result of immunohistochemistry:On PN7,there were no significantly difference in all the groups.On PN14,CaN expression in iodine-deficient groups were significantly higher than those of controls(P＜0.05).On PN21,CaN expression in 15ppmPTU and iodine-deficient groups were significantly higher than those of controls (P＜0.05).On PN28,CaN expression in 15ppmPTU and iodine-deficient groups were significantly higher than those of controls(P＜0.05),CaN expression in iodine-deficient groups were significantly higher than those of 5ppmPTU group(P＜0.05).On PN42, CaN expression in 15ppmPTU and iodine-deficient groups were significantly higher than those of controls(P＜0.05).
Conclusion
1、Iodine deficiency and hypothyroidism may effect pups development and lead to the body weights decrease and eye opening delay.
2、Iodine deficiency and hypothyroidism change cerebellar nerves development.
3、Iodine deficiency and hypothyroidism may reduce the expression of CaMKⅡ, CaM,and increase the expression of CaN in pup cerebellar cortex.
In summary,our results demonstrate that transient exposure to a period of iodine deficiency and hypothyroidism during a period of brain development changed cerebellar morphology and effected the expression of CaMKⅡ,CaM,and CaN.The changes are likely to impaired synaptic plasticity,effected the formation of normal neural circuit,and resulted in cerebellar development disturbance.
引文
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15 Monti B,Berteotti C,and Contestabile A.Dysregulation of memory-related proteins in the hippocampus of aged rats and their relation with cognitive impairment.Hippocampus,2005;15(8):1041-1049.
16 Aine Kelly,Serge Laroche,Sabrina Davis.Activation of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase in Hippocampal Circuitry Is Required for Consolidation and Reconsolidation of Recognition Memory.The Journal of Neuroscience,2003;12(23):5354-5360.
17 Poser S,Storm DR.Role of Ca~(2+)-stimulated adenylyl eyelases in LTP and memory formation.Int Dev Neurosci,2001;19(4):387-394.
18 Ran X,Miao HH,Sheu FS,et al.Structural and dynamic characterization of a neuron-specific protein kinase C substrate neurogranin.Biochemistry,2003;42(17):5143-5150.
19 Wu J,Huang KP,Huang FL.Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca~(2+)- and Ca~(2+)/calmodulin-dependent neuronal signaling in the hippocampus.J Neurochem,2003;86(6):1524-1533.
20 Limb(a|¨)ck-Stokin K,Korzus E,Nagaoka-Yasuda R,et al.Nuclear calcium/calmodulin regulates memory consolidation.J Neurosci,2004;24(48):10858-10867.
21 Manzano J,Morte B,Scanlan TS.Differential effects of triiodothyronine and the thyroid hormone receptor beta-specific agonist GC-1 on thyroid hormone target genes in the brain.Endocrinology,2003;144(12):5480-5487.
22 Pekary AE,Sattin A.Regulation of TRH and TRH-related peptides in rat brain by thyroid and steroid hormones.Peptides,2001;22(7):1161-1173.
23 陈祖培.当前碘缺乏病防治应当注意的问题.中国地方病学杂志,2004,23(3):193-194.
24 Chan S and Kilby MD.Thyroid hormone and central nervous system development.Journal of Endocrinology,2000;165(1):1-8.
25 Lazarus JH.Congenital hypothyroidism.Arch Dis Child,2005;90(2):112-113.26 Perez-Lopez FR.Iodine and thyroid hormones during pregnancy and postpartum.Gynecol Endocrinol,2007;23(7):414-428.
27 Forrest D.The developing brain and maternal thyroid hormone:finding the links.Endocrinology,2004;145(9):4034-4036.
28 王琨,陈祖培.碘与甲状腺功能及其相关疾病.中国地方病学杂志,2006;25(3):349-351.
29 Morreale de Escobar G,Obregon MJ and Escobar del Rey F.Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab,2000;85(11):3975-3987.
30 Morreale de Escobar G,Obregon MJ,Escobar del Rey F.Role of thyroid hormone during early brain development.Eur J Endocrinol,2004;151(3):25-37.
31 姜莹,刘万洋,董静等.碘缺乏对大鼠仔鼠小脑GAP-43表达的影响.毒理学杂志.2006,20(4):241-243.
32 Glinoer D.Clinical and biological consequences of iodine deficiency during pregnancy.Endocr Dev,2007;10:62-85.
33 Berbel P,Obregon M J,Bernal J,et al.Iodine supplementation during pregnancy:a public health challenge.Trends Endocrinol Metab,2007;18(9):338-343.
34 Gerges NZ,Alkadhi KA.Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus:MAPK involvement.Hippocampus,2004;14(1):40-45.
35 Rosenblum K.,Futter M.,Voss K,et al.The role of extracellular regulated kinases Ⅰ/Ⅱ in late-phase long-term potentiation.J.Neurosci,2002;22(13):5432-5441.
36 Calloni GW,Penno CA,Cordova FM,et al.Congenital hypothyroidism alters the phosphorylation of ERK1/2 and p38MAPK in the hippocampus of neonatal rats.Dev Brain Res,2005;154(1):141-145.
37 Sui L,Anderson WL,and Gilbert ME.Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampus area CA1 following developmental thyroid hormone insufficiency.Toxicological Sciences,2005;85(1):647-656.
38 Alzoubi KH and Alkadhi KA.A critical role of CREB in the impairment of late-phase LTP by adult onset hypothyroidism.Experimental Neurology,2007;203(1):63-71.
39 Dong J,Yin HB,Liu WY,et al.Congenital iodine deficiency and hypothyroidism impair LTP and decrease c-fos and c-jun expression in rat hippocampus.Neurotoxicology,2005;26(3):417-426.
40 Roberts CG,Ladenson PW.Hypothyroidism.Lancet,2004;363(9411):793-803.
41 朱自强,朱广瑾,徐成丽.甲状腺机能减退时神经颗粒素变化的研究进展.国外医学·生理、病理科学与临床分册,2004;24(6):520-523.
42 Auso E,Lavado-Autric R,Cuevas E,et al.A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration.Endocrinology,2004;145(9):4037-4047.
43 Cuevas E,Auso E,Telefont M,et al.Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of MGE-derived neurons.Eur.J.Neurosci,2005;22(3):541-551.
44 Sui L and Gilbert ME.Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CAlof the neonatal rat hippocampus.Endocrinology,2003;144(9):4195-4203.
45 Orojan I,Bakota L,Gulya K.Differential calmodulin gene expression in the nuclei of the rat midbrain--brain stem region.Acta Histochem,2006,108(6):455-462.
46 Susca A,Stea G,Mule G,et al.Polymerase chain reaction(PCR)identification of Aspergillus niger and Aspergillus tubingensis based on the calmodulin gene.Food Addit Contain,2007,24(10):1154-1160.
1 郝如松,侯玥,孙刚.甲状腺激素调节脑发育的分子机制.中华内分泌代谢杂志.2003,19(2):155-157.
2 Santiago-Fernandez P,Torres-Barahona R,Muela-Martinez JA,et al.Intelligence quotient and iodine intake:a cross-sectional study in children.J Clin Endocrinol Metab.2004,89(8):3851-3857.
3 Shibusawa N,Hashimoto K,Yamada M.Thyrotropin-releasing hormone(TRH) in the cerebellum.Cerebellum.2008;7(1):84-95.
4 Hasebe M,Matsumoto I,Imagawa T,et al.Effects of an anti-thyroid drug,methimazole,administration to rat dams on the cerebellar cortex development in their pups.Int J Dev Neurosci.2008;26(5):409-414.
5 Anderson GW.Thyroid hormone and cerebellar development.Cerebellum.2008;7(1):60-74.
6 Tompson CC,Dotter GB.Thyroid hormone action in neural development.Cerebral Cortex,2000,10(10):939-945.
7 Musas GC,Muass F,Bertto R,et al.Influence of thyroid in nervous system growth.Mnierva Pediatr.2001,53(4):325-353.
8 王淑秋,陶佳南,孟丹等.实验性甲状腺功能低下大鼠脑神经细胞超微结构变化.中国地方病学杂志,1996,15(4):219-220.
9 Lima FR,Gervais A,Colin C,et al.Regulation of microglial development a novel role for thyroid hormone.J Neurosci.2000,21(6):2028-2038.
10 C R Liu,L Y Li,F Shi,et al.Effects of hyper- and hypothyroid on expression of thyroid hormone receptor mRNA in rat myocardium.Journal of Endocrinology.2007,195(3):429-438.
11 Yen PM.Physiological and Molecular Basis of Thyroid Hormone Action.Physiological Reviews.2001,81(3):1097-1142.
12 Juan B.Thyroid hormone receptors in brain development and function.Nature Clinical Practice Endocrinology.2007,3(3):249-259.
13 Koenig RJ.Thyroid hormone receptor coactivators and corepressors.Thyroid,1998,8(8):703-713.
14 姜莹,陈杰,刘万洋等.碘缺乏对大鼠仔鼠小脑c-fos和c-jun蛋白表达的影响.环境与健康杂志.2006,23(5):225-227.
15 姜莹,刘万洋,董静等.碘缺乏对大鼠仔鼠小脑GAP-43表达的影响.毒理学杂志.2006,20(4):241-243.
16 Lima FR,Gervais A,Colin C,et al.Regulation of microglial development:A Novel Role for Thyroid Hormone.J Neurosci.2001,21(6):2028-2038.
17 Heuer H,Mason CA.Thyroid hormone induces cerebellar Purkinje cell dendritic development via the thyroid hormone receptor alphal.J Neurosci,2003,23(33):10604-10612.
18 Kimura-Kuroda J,Nagata I,Negishi-Kato M,et al.Thyroid hormone-dependent development of mouse cerebellar Purkinje cells in vitro.Brain Res Dev Brain Res,2002,137(1):55-65.
19 Bozon B,Kelly A,Josselyn SA.MAPK,CREB and zif268 are all required for the consolidation of recognition memory.Philos Trans R Soc Lond B Biol Sci.2003,358(1432):805-814.
20 Wu GY,Deisseroth K,Tsien RW.Spaced stimulistabilize MAPK pathway activation and its effects ondendritic morphology.Nat Neurosci.2001,4(2):151-158.
21 张洪梅,苏青.甲状腺激素调节小脑发育的机制.国外医学内分泌学分册.2005,25(6):367-370.
22 Darras VM.Endocrine disrupting polyhalogenated organic pollutants interfere with thyroid hormone signalling in the developing brain.Cerebellum.2008;7(1):26-37.
23 Mendes-de-Aguiar CB,Costa-Silva B,Alvarez-Silva M,et al.Thyroid hormone mediates syndecan expression in rat neonatal cerebellum.Cell Mol Neurobiol.2008;28(6):795-801.
24 Larry IB,Aryeh R.GAP-43:an intrinsic determinant of neuronal development and plasticity.TINS,1997,20(2):84-91.
25 Catherine C,Thompson,Gregory B,et al.Thyroid hormone action in neural development.Cerebral Cortex.2000,10(10):939-945.
2 Gilbert ME.Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism.Brain Res Dev Brain Res,2004;148(1):11-18.
3 Kibirige MS,Hutchison S,Owen CJ,et al.Prevalence of maternal dietary iodine insufficiency in the north east of England:implications for the fetus.Arch Dis Child Fetal Neonatal Ed,2004;89(5):436-439.
4 陈祖培.对全民食盐加碘防治碘缺乏病的评价.国外医学.内分泌学分册,2002;22(4):268-271.
5 中红梅.全球碘缺乏病流行现状.中国地方病学杂志,2005,24(5):587-589.
6 Chrobak JJ,Lorincz A,Buzsaki G.Physiological patterns in the hippocampo-entorhinal cortex system.Hippocampus,2000;10(4):457-464.
7 Hebert AE,Dash PK.Nonredundant roles for hippocampal and entorhinal cortical plasticity in spatial memory storage.Pharmacology,Biochemistry and Behavior,2004;79(1):143-153.
8 Sawada K,Kalam Azad A,Sakata-Haga H,et al.Striking pattern of Purkinje cell loss in cerebellum of an ataxic mutant mouse,tottering.Acta Neurobiol Exp(Wars).2009;69(1):138-183.
9 Feld M,Dimant B,Delorenzi A,et al.Phosphorylation of extra-nuclear ERK /MAPK is required for long-term memory consolidation in the crab Chasmagnathus.Behavioural Brain Res,2005;158(2):251-261.
10 Cullen PJ,Lockyer PJ.Intergration of calcium and Ras signaling.Nat Rev Moll Cell Biol,2002;3(5):339-348.
11 Koibuchi N,The role of thyroid hormone on cerebellar development.Cerebellum.2008;7(4):530-533.
12 Lante F,de Jesus Ferreira MC,Guiramand J,et al.Low-frequency stimulation induces a new form of LTP,metabotropic glutamate(mGlu5) receptor- and PKA-dependent,in the CA1 area of the rat hippocampus.Hippocampus,2006;16(4):345-360.
13 Bozon B,Kelly A,Josselyn SA,et al.MAPK,CREB and zif268 are all required for the consolidation of recognition memory.Philos Trans R Soc Lond B Biol Sci,2003;358(1432):805-814.
14 Takahashi M,Negishi T,Tashiro T.Identification of genes mediating thyroid hormone action in the developing mouse cerebellum.J Neurochem.2008;104(3):640-652.
15 Monti B,Berteotti C,and Contestabile A.Dysregulation of memory-related proteins in the hippocampus of aged rats and their relation with cognitive impairment.Hippocampus,2005;15(8):1041-1049.
16 Aine Kelly,Serge Laroche,Sabrina Davis.Activation of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase in Hippocampal Circuitry Is Required for Consolidation and Reconsolidation of Recognition Memory.The Journal of Neuroscience,2003;12(23):5354-5360.
17 Poser S,Storm DR.Role of Ca~(2+)-stimulated adenylyl eyelases in LTP and memory formation.Int Dev Neurosci,2001;19(4):387-394.
18 Ran X,Miao HH,Sheu FS,et al.Structural and dynamic characterization of a neuron-specific protein kinase C substrate neurogranin.Biochemistry,2003;42(17):5143-5150.
19 Wu J,Huang KP,Huang FL.Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca~(2+)- and Ca~(2+)/calmodulin-dependent neuronal signaling in the hippocampus.J Neurochem,2003;86(6):1524-1533.
20 Limb(a|¨)ck-Stokin K,Korzus E,Nagaoka-Yasuda R,et al.Nuclear calcium/calmodulin regulates memory consolidation.J Neurosci,2004;24(48):10858-10867.
21 Manzano J,Morte B,Scanlan TS.Differential effects of triiodothyronine and the thyroid hormone receptor beta-specific agonist GC-1 on thyroid hormone target genes in the brain.Endocrinology,2003;144(12):5480-5487.
22 Pekary AE,Sattin A.Regulation of TRH and TRH-related peptides in rat brain by thyroid and steroid hormones.Peptides,2001;22(7):1161-1173.
23 陈祖培.当前碘缺乏病防治应当注意的问题.中国地方病学杂志,2004,23(3):193-194.
24 Chan S and Kilby MD.Thyroid hormone and central nervous system development.Journal of Endocrinology,2000;165(1):1-8.
25 Lazarus JH.Congenital hypothyroidism.Arch Dis Child,2005;90(2):112-113.26 Perez-Lopez FR.Iodine and thyroid hormones during pregnancy and postpartum.Gynecol Endocrinol,2007;23(7):414-428.
27 Forrest D.The developing brain and maternal thyroid hormone:finding the links.Endocrinology,2004;145(9):4034-4036.
28 王琨,陈祖培.碘与甲状腺功能及其相关疾病.中国地方病学杂志,2006;25(3):349-351.
29 Morreale de Escobar G,Obregon MJ and Escobar del Rey F.Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab,2000;85(11):3975-3987.
30 Morreale de Escobar G,Obregon MJ,Escobar del Rey F.Role of thyroid hormone during early brain development.Eur J Endocrinol,2004;151(3):25-37.
31 姜莹,刘万洋,董静等.碘缺乏对大鼠仔鼠小脑GAP-43表达的影响.毒理学杂志.2006,20(4):241-243.
32 Glinoer D.Clinical and biological consequences of iodine deficiency during pregnancy.Endocr Dev,2007;10:62-85.
33 Berbel P,Obregon M J,Bernal J,et al.Iodine supplementation during pregnancy:a public health challenge.Trends Endocrinol Metab,2007;18(9):338-343.
34 Gerges NZ,Alkadhi KA.Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus:MAPK involvement.Hippocampus,2004;14(1):40-45.
35 Rosenblum K.,Futter M.,Voss K,et al.The role of extracellular regulated kinases Ⅰ/Ⅱ in late-phase long-term potentiation.J.Neurosci,2002;22(13):5432-5441.
36 Calloni GW,Penno CA,Cordova FM,et al.Congenital hypothyroidism alters the phosphorylation of ERK1/2 and p38MAPK in the hippocampus of neonatal rats.Dev Brain Res,2005;154(1):141-145.
37 Sui L,Anderson WL,and Gilbert ME.Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampus area CA1 following developmental thyroid hormone insufficiency.Toxicological Sciences,2005;85(1):647-656.
38 Alzoubi KH and Alkadhi KA.A critical role of CREB in the impairment of late-phase LTP by adult onset hypothyroidism.Experimental Neurology,2007;203(1):63-71.
39 Dong J,Yin HB,Liu WY,et al.Congenital iodine deficiency and hypothyroidism impair LTP and decrease c-fos and c-jun expression in rat hippocampus.Neurotoxicology,2005;26(3):417-426.
40 Roberts CG,Ladenson PW.Hypothyroidism.Lancet,2004;363(9411):793-803.
41 朱自强,朱广瑾,徐成丽.甲状腺机能减退时神经颗粒素变化的研究进展.国外医学·生理、病理科学与临床分册,2004;24(6):520-523.
42 Auso E,Lavado-Autric R,Cuevas E,et al.A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration.Endocrinology,2004;145(9):4037-4047.
43 Cuevas E,Auso E,Telefont M,et al.Transient maternal hypothyroxinemia at onset of corticogenesis alters tangential migration of MGE-derived neurons.Eur.J.Neurosci,2005;22(3):541-551.
44 Sui L and Gilbert ME.Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CAlof the neonatal rat hippocampus.Endocrinology,2003;144(9):4195-4203.
45 Orojan I,Bakota L,Gulya K.Differential calmodulin gene expression in the nuclei of the rat midbrain--brain stem region.Acta Histochem,2006,108(6):455-462.
46 Susca A,Stea G,Mule G,et al.Polymerase chain reaction(PCR)identification of Aspergillus niger and Aspergillus tubingensis based on the calmodulin gene.Food Addit Contain,2007,24(10):1154-1160.
1 郝如松,侯玥,孙刚.甲状腺激素调节脑发育的分子机制.中华内分泌代谢杂志.2003,19(2):155-157.
2 Santiago-Fernandez P,Torres-Barahona R,Muela-Martinez JA,et al.Intelligence quotient and iodine intake:a cross-sectional study in children.J Clin Endocrinol Metab.2004,89(8):3851-3857.
3 Shibusawa N,Hashimoto K,Yamada M.Thyrotropin-releasing hormone(TRH) in the cerebellum.Cerebellum.2008;7(1):84-95.
4 Hasebe M,Matsumoto I,Imagawa T,et al.Effects of an anti-thyroid drug,methimazole,administration to rat dams on the cerebellar cortex development in their pups.Int J Dev Neurosci.2008;26(5):409-414.
5 Anderson GW.Thyroid hormone and cerebellar development.Cerebellum.2008;7(1):60-74.
6 Tompson CC,Dotter GB.Thyroid hormone action in neural development.Cerebral Cortex,2000,10(10):939-945.
7 Musas GC,Muass F,Bertto R,et al.Influence of thyroid in nervous system growth.Mnierva Pediatr.2001,53(4):325-353.
8 王淑秋,陶佳南,孟丹等.实验性甲状腺功能低下大鼠脑神经细胞超微结构变化.中国地方病学杂志,1996,15(4):219-220.
9 Lima FR,Gervais A,Colin C,et al.Regulation of microglial development a novel role for thyroid hormone.J Neurosci.2000,21(6):2028-2038.
10 C R Liu,L Y Li,F Shi,et al.Effects of hyper- and hypothyroid on expression of thyroid hormone receptor mRNA in rat myocardium.Journal of Endocrinology.2007,195(3):429-438.
11 Yen PM.Physiological and Molecular Basis of Thyroid Hormone Action.Physiological Reviews.2001,81(3):1097-1142.
12 Juan B.Thyroid hormone receptors in brain development and function.Nature Clinical Practice Endocrinology.2007,3(3):249-259.
13 Koenig RJ.Thyroid hormone receptor coactivators and corepressors.Thyroid,1998,8(8):703-713.
14 姜莹,陈杰,刘万洋等.碘缺乏对大鼠仔鼠小脑c-fos和c-jun蛋白表达的影响.环境与健康杂志.2006,23(5):225-227.
15 姜莹,刘万洋,董静等.碘缺乏对大鼠仔鼠小脑GAP-43表达的影响.毒理学杂志.2006,20(4):241-243.
16 Lima FR,Gervais A,Colin C,et al.Regulation of microglial development:A Novel Role for Thyroid Hormone.J Neurosci.2001,21(6):2028-2038.
17 Heuer H,Mason CA.Thyroid hormone induces cerebellar Purkinje cell dendritic development via the thyroid hormone receptor alphal.J Neurosci,2003,23(33):10604-10612.
18 Kimura-Kuroda J,Nagata I,Negishi-Kato M,et al.Thyroid hormone-dependent development of mouse cerebellar Purkinje cells in vitro.Brain Res Dev Brain Res,2002,137(1):55-65.
19 Bozon B,Kelly A,Josselyn SA.MAPK,CREB and zif268 are all required for the consolidation of recognition memory.Philos Trans R Soc Lond B Biol Sci.2003,358(1432):805-814.
20 Wu GY,Deisseroth K,Tsien RW.Spaced stimulistabilize MAPK pathway activation and its effects ondendritic morphology.Nat Neurosci.2001,4(2):151-158.
21 张洪梅,苏青.甲状腺激素调节小脑发育的机制.国外医学内分泌学分册.2005,25(6):367-370.
22 Darras VM.Endocrine disrupting polyhalogenated organic pollutants interfere with thyroid hormone signalling in the developing brain.Cerebellum.2008;7(1):26-37.
23 Mendes-de-Aguiar CB,Costa-Silva B,Alvarez-Silva M,et al.Thyroid hormone mediates syndecan expression in rat neonatal cerebellum.Cell Mol Neurobiol.2008;28(6):795-801.
24 Larry IB,Aryeh R.GAP-43:an intrinsic determinant of neuronal development and plasticity.TINS,1997,20(2):84-91.
25 Catherine C,Thompson,Gregory B,et al.Thyroid hormone action in neural development.Cerebral Cortex.2000,10(10):939-945.