Department of Biology, Georgia State University, Atlanta, Georgia.
Department of Biology, Georgia State University, Atlanta, Georgia
Am J Physiol Cell Physiol. 2014 Sep 15;307(6):C508-20. doi: 10.1152/ajpcell.00035.2014. Epub 2014 Jul 9.
Rett syndrome is an autism-spectrum disorder resulting from mutations to the X-linked gene, methyl-CpG binding protein 2 (MeCP2), which causes abnormalities in many systems. It is possible that the body may develop certain compensatory mechanisms to alleviate the abnormalities. The norepinephrine system originating mainly in the locus coeruleus (LC) is defective in Rett syndrome and Mecp2-null mice. LC neurons are subject to modulation by GABA, glutamate, and acetylcholine (ACh), providing an ideal system to test the compensatory hypothesis. Here we show evidence for potential compensatory modulation of LC neurons by post- and presynaptic ACh inputs. We found that the postsynaptic currents of nicotinic ACh receptors (nAChR) were smaller in amplitude and longer in decay time in the Mecp2-null mice than in the wild type. Single-cell PCR analysis showed a decrease in the expression of α3-, α4-, α7-, and β3-subunits and an increase in the α5- and α6-subunits in the mutant mice. The α5-subunit was present in many of the LC neurons with slow-decay nAChR currents. The nicotinic modulation of spontaneous GABAA-ergic inhibitory postsynaptic currents in LC neurons was enhanced in Mecp2-null mice. In contrast, the nAChR manipulation of glutamatergic input to LC neurons was unaffected in both groups of mice. Our current-clamp studies showed that the modulation of LC neurons by ACh input was reduced moderately in Mecp2-null mice, despite the major decrease in nAChR currents, suggesting possible compensatory processes may take place, thus reducing the defects to a lesser extent in LC neurons.
雷特综合征是一种自闭症谱系障碍，源自 X 连锁基因甲基-CpG 结合蛋白 2（MeCP2）的突变，导致许多系统异常。身体可能会发展出某些补偿机制来减轻异常。起源于蓝斑核（LC）的去甲肾上腺素系统在雷特综合征和 MeCP2 缺失小鼠中存在缺陷。LC 神经元受到 GABA、谷氨酸和乙酰胆碱（ACh）的调制，为测试补偿假说提供了一个理想的系统。在这里，我们提供了 LC 神经元的突触前和突触后 ACh 输入可能存在补偿性调节的证据。我们发现，MeCP2 缺失小鼠的烟碱型乙酰胆碱受体（nAChR）的突触后电流幅度较小，衰减时间较长。单细胞 PCR 分析显示，突变小鼠中α3、α4、α7 和β3 亚基的表达减少，而α5 和α6 亚基的表达增加。α5 亚基存在于具有慢衰减 nAChR 电流的许多 LC 神经元中。MeCP2 缺失小鼠中 LC 神经元中自发 GABA 能抑制性突触后电流的烟碱调制增强。相反，两组小鼠的 LC 神经元中谷氨酸能输入的 nAChR 操作不受影响。我们的电流钳研究表明，尽管 nAChR 电流明显减少，但 LC 神经元的 ACh 输入的调制在 MeCP2 缺失小鼠中适度降低，这表明可能发生了补偿过程，从而使 LC 神经元的缺陷程度降低到较小程度。
