Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital

Abstract

Rett syndrome is a neurodevelopmental disorder that usually arises from mutations or deletions in methyl-CpG binding protein 2 (MeCP2), a transcriptional regulator that affects neuronal development and maturation without causing cell loss. Here, we show that silencing of MeCP2 decreased neurite arborization and synaptogenesis in cultured hippocampal neurons from rat fetal brains. These structural defects were associated with alterations in synaptic transmission and neural network activity. Similar retardation of dendritic growth was also observed in MeCP2-deficient newborn granule cells in the dentate gyrus of adult mouse brains in vivo, demonstrating direct and cell-autonomous effects on individual neurons. These defects, caused by MeCP2 deficiency, were reversed by treatment with the US Food and Drug Administration-approved drug, pentobarbital, in vitro and in vivo, possibly caused by modulation of γ-aminobutyric acid signaling. The results indicate that drugs modulating γ-aminobutyric acid signaling are potential therapeutics for Rett syndrome.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-015-0343-0) contains supplementary material, which is available to authorized users.

Choline Ameliorates Disease Phenotypes in Human iPSC Models of Rett Syndrome

“…We first examined the structural properties of iPSC-derived RTT neurons; it is known that neurons with RTT mutations have smaller cell bodies (Bauman et al 1995;Ma et al 2015). We similarly observed smaller soma area in the iPSC-derived RTT neurons-the somatic area of cells in the RTT1 and RTT2 lines was significantly smaller (by 20-25 %) relative to the CTRL cells (Fig.…”

“…Given the physiological roles of choline as the precursor of major cellular membrane components and acetylcholine, the neurotransmitter of cholinergic neurons, it is possible that choline can compensate for the pathophysiology of RTT. Mouse and cellular models of RTT, including the human-derived RTT iPSCs shown here, reportedly have fewer synapses (Fukuda et al 2005;Chao et al 2007;Marchetto et al 2010a;Ma et al 2015). Therefore, we examined whether choline supplementation can ameliorate these defects in synapse formation observed in the RTT neurons by counting the density of Syn1 ?…”

“…A major pathomorphological abnormality in RTT is a 12-34 % decrease in brain weight and volume (Armstrong 2005). Individual neurons from RTT brains also have structural defects, including smaller soma size, reduced dendritic arborizations as well as reduced synapse number and functions (Bauman et al 1995;Casanova et al 2003;Armstrong 2005;Ma et al 2015). Given the physiological roles of choline as the precursor of major cellular membrane components, it is possible that this micronutrient could compensate for the pathophysiology of RTT.…”

Integrated analysis of a compendium of RNA-Seq datasets for splicing factors

“…Here, the knockdown of Cirbp by shRNAs was efficient, as confirmed by the qRT-PCR assays (Figure S4b). We analyzed the neuronal morphology of primary hippocampal neurons isolated from embryonic stage 18 (E18) rats, where replicates of neurons were examined from three groups of neurons, namely Mecp2 knockdown, Cirbp, and Mecp2 double knockdown, and the control (see Methods section) 24,25,26,27 . The representative neuronal images depict the neuron morphology for three groups of neurons (Figure 3a).…”

Rett syndrome: a sex-biased neurodevelopmental disorder

“…Subsequent effort was then directed to targeting mechanisms affecting neuronal growth and functions. Compounds such as pentobarbital was used to modulate γ-aminobutyric acid (GABA) class A receptor signalling so as to enhance the growth and synaptic functions of neurons 9 . Nutritional compounds such as choline could possibly work by changing the phospholipids composition in cell membranes and enhancing acetylcholine production, which are both affected in Rett syndrome models 10 .…”