Deng Jinbo, Elberger Andrea J
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, TN38163, USA.
Brain Res Dev Brain Res. 2003 Sep 10;144(2):135-50. doi: 10.1016/s0165-3806(03)00157-3.
Offspring of transgenic mice with deletion of the NMDA-NR1 (NR1) receptor received prenatal alcohol exposure during most of gestation. Before and after birth, offspring were sacrificed in order to examine the morphological consequences of the prenatal exposure. Previously, we reported that the dendritic arborization of corpus callosum projection neurons (CCpn) in visual cortex was abnormal in rats given prenatal alcohol exposure; the effects were dose-dependent [Neurotoxicol. Teratol. 24 (2002) 719-732]. The same parameters were examined in the transgenic mice. Crystals of DiI were placed into the CC of mice at different ages that had been prenatally exposed to alcohol. Controls included untreated transgenic mice, and transgenic mice with the same nutritional and handling stressors. Compared to Controls, prenatal alcohol exposure caused the NR1+/+ mice to expand the dendritic arbor of CCpn in visual cortex. The dendritic arbors had increased branch numbers and length; these increases were dose-dependent. In contrast, the prenatally exposed NR1-/- mice showed normal dendritic arbors with all prenatal alcohol doses. In addition, prenatal alcohol exposure was found to have morbidity and teratogenic effects on offspring. In seven separate indicators of the effects of prenatal alcohol exposure, only one indicator was present but reduced in NR1-/- offspring, indicating that total deletion of the NMDA-NR1 receptor throughout development largely blocks but sometimes attenuates the effects of prenatal alcohol exposure. Similarly, in seven separate indicators of the effects of prenatal alcohol exposure, five indicators were attenuated in NR1+/- compared to NR1+/+ offspring, although affected more than in NR1-/-; this suggests a gene-dose effect. The results indicate that functional NMDA-NR1 receptors are necessary for the neurotoxic and teratogenic effects of prenatal alcohol exposure. This study will aid in understanding how the NMDA receptors play an important role in prenatal alcohol effects on brain development.
缺失N-甲基-D-天冬氨酸（NMDA）-NR1受体的转基因小鼠的后代在孕期的大部分时间里都受到了产前酒精暴露。在出生前后，对后代实施安乐死以检查产前暴露的形态学后果。此前，我们报道了产前酒精暴露的大鼠视皮层胼胝体投射神经元（CCpn）的树突分支异常；这些影响具有剂量依赖性[《神经毒理学与致畸学》24（2002年）719 - 732页]。在转基因小鼠中检查了相同的参数。将DiI晶体置于不同年龄且产前暴露于酒精的小鼠的胼胝体中。对照组包括未处理的转基因小鼠以及具有相同营养和处理应激因素的转基因小鼠。与对照组相比，产前酒精暴露使NR1+/+小鼠视皮层中CCpn的树突分支扩展。树突分支的数量和长度增加；这些增加具有剂量依赖性。相比之下，产前暴露的NR1-/-小鼠在所有产前酒精剂量下均显示正常的树突分支。此外，发现产前酒精暴露对后代有发病和致畸作用。在产前酒精暴露影响的七个独立指标中，NR1-/-后代仅出现一个指标但有所降低，这表明在整个发育过程中NMDA-NR1受体的完全缺失在很大程度上阻断了但有时会减弱产前酒精暴露的影响。同样，在产前酒精暴露影响的七个独立指标中，与NR1+/+后代相比，NR1+/-后代中有五个指标减弱，尽管其受影响程度大于NR1-/-；这表明存在基因剂量效应。结果表明，功能性NMDA-NR1受体对于产前酒精暴露的神经毒性和致畸作用是必需的。这项研究将有助于理解NMDA受体在产前酒精对大脑发育影响中如何发挥重要作用。
