Department of Neuroscience and Experimental Therapeutics, Texas A&M University System Health Science Center, Medical Research and Education Building, 8447 State Highway 47, Bryan, TX 77807-3260, USA.
Neuroscience. 2012 Dec 6;225:105-17. doi: 10.1016/j.neuroscience.2012.09.002. Epub 2012 Sep 12.
Chronic exposure to nicotine during the first postnatal week in rats, a developmental period that corresponds to the third trimester of human gestation, results in sexually dimorphic long-term functional defects in the adult hippocampus. One potential cause could be the sex-specific differences in the maturation of GABA(A) receptor-mediated responses from excitatory to inhibitory, which depends on the expression of the Na(2+)/K(+)/Cl(-) co-transporter 1 (NKCC1) and the K(+)/Cl(-) co-transporter 2 (KCC2). In the rat hippocampus, this switch occurs during the first and second postnatal week in females and males, respectively, and is regulated by nicotinic receptor activation. Excitatory GABAergic signaling can increase brain-derived neurotrophic factor (BDNF) expression, which might exacerbate sex differences by impacting synaptogenesis. We hypothesized that chronic neonatal nicotine (CNN) exposure differentially regulates the expression of these co-transporters and BDNF in males and females. We use quantitative isotopic in situ hybridization to examine the expression of mRNAs for NKCC1, KCC2, BDNF, and NMDA receptor subunit 2A (NR2A) and NMDA receptor subunit 2B (NR2B) in the postnatal day (P) 5 and 8 rat hippocampi in both sexes that were either control-treated or with 6mg/kg/day nicotine in milk formula (CNN) via gastric intubation starting at P1. In line with prolonged GABAergic excitation, we found that at P5 males had significantly higher mRNA expression of NKCC1 and BDNF than females. CNN treatment resulted in a significant increase in KCC2 and BDNF mRNA expression in male but not female hippocampus (p<0.05). Males also had higher expression of NR2A and lower expression of NR2B at P5 compared to females (p<0.05). At P8, there were neither sex nor treatment effects on mRNA expression, indicating the end of a critical period for sensitivity to nicotine. These results suggest that differential maturation of GABA(A)R-mediated responses result in sex-specific sensitivity to nicotine during early postnatal development, potentially explaining the differential long-term effects of CNN on hippocampal function.
在大鼠出生后的第一周内持续接触尼古丁，这一发育阶段相当于人类妊娠的第三个 trimester，会导致成年海马体出现长期的性别二态性功能缺陷。一个潜在的原因可能是 GABA(A) 受体介导的反应从兴奋性到抑制性的成熟存在性别特异性差异，这取决于 Na(2+)/K(+)/Cl(-) 共转运蛋白 1 (NKCC1) 和 K(+)/Cl(-) 共转运蛋白 2 (KCC2) 的表达。在大鼠海马体中，这种转变分别发生在雌性和雄性的第一和第二 postnatal 周，并且受烟碱型乙酰胆碱受体激活的调节。兴奋性 GABA 能信号可以增加脑源性神经营养因子 (BDNF) 的表达，这可能通过影响突触发生来加剧性别差异。我们假设慢性新生尼古丁 (CNN) 暴露在雄性和雌性中以不同的方式调节这些共转运蛋白和 BDNF 的表达。我们使用定量同位素原位杂交技术来检测 NKCC1、KCC2、BDNF 和 NMDA 受体亚基 2A (NR2A) 和 NMDA 受体亚基 2B (NR2B) 在出生后第 5 天和第 8 天的雄性和雌性大鼠海马体中的 mRNA 表达，这些大鼠在出生后第 1 天通过胃内灌注接受了控制处理或 6mg/kg/天的尼古丁。与 GABA 能兴奋持续时间延长一致，我们发现，在 P5 时，雄性的 NKCC1 和 BDNF mRNA 表达明显高于雌性。CNN 处理导致雄性海马体中 KCC2 和 BDNF mRNA 表达显著增加，但雌性海马体中则没有 (p<0.05)。与雌性相比，雄性在 P5 时还具有更高的 NR2A 表达和更低的 NR2B 表达 (p<0.05)。在 P8 时，mRNA 表达既没有性别差异也没有处理效应，表明对尼古丁敏感性的关键时期已经结束。这些结果表明，GABA(A)R 介导的反应的不同成熟导致了新生后早期发育过程中对尼古丁的性别特异性敏感性，这可能解释了 CNN 对海马体功能的不同长期影响。
