Psychiatry Department, Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, United States; Psychiatry Department, Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
Departamento de Fisiologia, Programa de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de Sergipe, São Cristóvão, Brazil.
Dev Biol. 2024 Nov;515:112-120. doi: 10.1016/j.ydbio.2024.07.010. Epub 2024 Jul 22.
Hormonal imbalance during pregnancy is a risk factor for neuropsychiatric impairment in the offspring. It has been suggested that hypothyroidism leads to dysfunction of cortical GABAergic interneurons and inhibitory system development that in turn underlies impairment of the central nervous system. Here we investigated how gestational hypothyroidism affected offspring GABAergic system development as well as redox regulation parameters, because of previous links identified between the two. Experimental Gestational Hypothyroidism (EGH) was induced in CD-1 mice with 0.02% methimazole (MMI) in drinking water from embryonic day 9 (E9) until tissue collection at embryonic day 14 (E14) or E18. We examined GABAergic cell distribution and inhibitory system development gene expression as well as redox relevant gene expression and direct measures across all embryos regardless of sex. Intrauterine restriction of maternal thyroid hormones significantly impacted both of these outcomes in brain, as well as altering redox regulation in the placenta. GAD67+ neuronal migration was reduced, accompanied by a disruption in gene expression influencing GABAergic cell migration and cortical inhibitory neural system development. EGH also altered embryonic brain gene expression of Gpx1, Nfe2l2, Cat levels in the dorsal E14 brains. Additionally, EGH resulted in elevated TBARS, Gpx1 and Nfe2l2 in the ventral E18 brains. Furthermore, EGH downregulated placental Gpx1 gene expression at E14 and increased protein oxidation at E18. These findings support the hypothesis that sufficient maternal thyroid hormone supply to the fetus influences central nervous system development, including processes of GABAergic system development and redox equilibrium.
孕期激素失衡是后代神经精神损伤的一个风险因素。有研究表明，甲状腺功能减退症导致皮质 GABA 能中间神经元和抑制系统发育功能障碍，进而导致中枢神经系统损伤。在这里，我们研究了妊娠期甲状腺功能减退症如何影响后代 GABA 能系统的发育以及氧化还原调节参数，因为之前已经确定了这两者之间存在联系。在 CD-1 小鼠中，通过在饮用水中添加 0.02%的甲巯咪唑（MMI）从胚胎第 9 天（E9）到胚胎第 14 天（E14）或第 18 天（E18）诱导实验性妊娠期甲状腺功能减退症（EGH）。我们检查了 GABA 能细胞分布和抑制系统发育基因表达以及所有胚胎的氧化还原相关基因表达和直接测量，无论性别如何。宫内限制母体甲状腺激素的供应显著影响了大脑中的这两种结果，同时也改变了胎盘的氧化还原调节。GAD67+神经元迁移减少，同时影响 GABA 能细胞迁移和皮质抑制性神经网络发育的基因表达也受到干扰。EGH 还改变了 E14 大脑中胚胎的 Gpx1、Nfe2l2、Cat 基因表达。此外，EGH 导致 E18 大脑中的 TBARS、Gpx1 和 Nfe2l2 升高。此外，EGH 还降低了 E14 胎盘 Gpx1 基因表达，并增加了 E18 胎盘的蛋白质氧化。这些发现支持这样一种假设，即母体甲状腺激素向胎儿的充分供应会影响中枢神经系统的发育，包括 GABA 能系统的发育和氧化还原平衡过程。
