Abstract
Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls, with 95% of RTT cases resulting from mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Choline, a dietary micronutrient found in most foods, has been shown to be important for brain development and function. However, the exact effects and mechanisms are still unknown. We found that 13 mg/day (1.7 × required daily intake) of postnatal choline treatment to Mecp2-conditional knockout mice rescued not only deficits in motor coordination, but also their anxiety-like behaviour and reduced social preference. Cortical neurons in the brains of Mecp2-conditional knockout mice supplemented with choline showed enhanced neuronal morphology and increased density of dendritic spines. Modelling RTT in vitro by knocking down the expression of the MeCP2 protein with shRNA, we found that choline supplementation to MeCP2-knockdown neurons increased their soma sizes and the complexity of their dendritic arbors. Rescue of the morphological defects could lead to enhanced neurotransmission, as suggested by an observed trend of increased expression of synaptic proteins and restored miniature excitatory postsynaptic current frequency in choline-supplemented MeCP2-knockdown neurons. Through the use of specific inhibitors targeting each of the known physiological pathways of choline, synthesis of phosphatidylcholine from choline was found to be essential in bringing about the changes seen in the choline-supplemented MeCP2-knockdown neurons. Taken together, these data reveal a role of choline in modulating neuronal plasticity, possibly leading to behavioural changes, and hence, a potential for using choline to treat RTT.
Highlights
Rett syndrome (RTT) (OMIM 312750) is a postnatal neurodevelopmental disorder
To investigate the effects of choline supplementation in a behaving animal, we crossed Mecp2-floxed mice with a line expressing Cre recombinase under the CaMKIIα promoter. This generated animals with the Mecp2 gene deleted in the excitatory neurons of the forebrain. This model was chosen as previous studies have shown that the selective loss of MeCP2 in the forebrain was sufficient for the recapitulation of many of the behavioural phenotypes of RTT [22, 23]
The animals were supplemented with choline in their drinking water from postnatal day 1 (P1) to postnatal day 21 (P21)
Summary
Rett syndrome (RTT) (OMIM 312750) is a postnatal neurodevelopmental disorder. It is the second leading cause of mental retardation in girls, with an incidence rate of approximately. There is, a need to explore alternative means for the treatment of RTT. Supplementation of choline, a common dietary micronutrient, to various mouse models of RTT markedly improved their motoric function [18, 19]. The exact mechanism of how choline leads to improved function has not been comprehensively dissociated. This can have important ramifications on finding novel therapeutic strategies for RTT. We sought to examine the effects of choline on the various functional aspects of RTT, and to elucidate a possible mechanism of action of choline
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call