Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome

作者：Oginsky Max F; Cui Ningren; Zhong Weiwei; Johnson Christopher M; Jiang Chun^*

来源：American Journal of Physiology - Cell Physiology, 2014, 307(6): C508-C520.

DOI：10.1152/ajpcell.00035.2014

• acetylcholine
• nicotinic acetylcholine receptor
• compensatory mechanisms
• locus coeruleus
• Mecp2
• Rett syndrome

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 alpha(3)-, alpha(4)-, alpha(7)-, and beta(3)-subunits and an increase in the alpha(5)- and alpha(6)-subunits in the mutant mice. The alpha(5)-subunit was present in many of the LC neurons with slow-decay nAChR currents. The nicotinic modulation of spontaneous GABA(A)-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.

• 出版日期2014-9-15