The impact of MeCP2 loss- or gain-of-function on synaptic plasticity

Abstract

Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator of gene expression that is an important epigenetic factor in the maintenance and development of the central nervous system. The neurodevelopmental disorders Rett syndrome and MECP2 duplication syndrome arise from loss-of-function and gain-of-function alterations in MeCP2 expression, respectively. Several animal models have been developed to recapitulate the symptoms of Rett syndrome and MECP2 duplication syndrome. Cell morphology, neurotransmission, and cellular processes that support learning and memory are compromised as a result of MeCP2 loss- or gain-of-function. Interestingly, loss-of-MeCP2 function and MeCP2 overexpression trigger diametrically opposite changes in synaptic transmission. These findings indicate that the precise regulation of MeCP2 expression is a key requirement for the maintenance of synaptic and neuronal homeostasis and underscore its importance in central nervous system function. This review highlights the functional role of MeCP2 in the brain as a regulator of synaptic and neuronal plasticity as well as its etiological role in the development of Rett syndrome and MECP2 duplication syndrome.

Figures

Figure 1

Schematic representation of the cellular effects of MeCP2 loss- or gain-of-function. Miniature excitatory postsynaptic current (mEPSC) frequency is bidirectionally affected by decreased or increased MeCP2 expression with a positive correlation between levels of MeCP2 expression and spontaneous excitatory transmission. Short-term plasticity as measured by paired pulse stimulation is also bidirectionally regulated by MeCP2 expression with decreased expression and increased expression resulting in increased and decreased neurotransmitter release probability, respectively. Dendritic spine density is significantly altered by MeCP2 levels with decreased expression associated with lower spine density and increased expression associated with greater spine density (although lower spine density has also been reported following MeCP2 overexpression (Chapleau et al, 2009)). Long-term potentiation (LTP) does not appear bidirectionally influenced by MeCP2 expression as both knockout and overexpressing mice show similar deficits in LTP magnitude and maintenance (but see also Collins et al, 2004).

Figure 2

The role of MeCP2 in the regulation of neurotransmission. One hypothesis is that the level of MeCP2 expression titrates synaptic gene expression, which in turn alters neurotransmission in a proportional manner. (a) Our findings suggest that loss of MeCP2 increases gene expression of synaptic genes and alters neurotransmission, specifically a decrease in spontaneous excitatory neurotransmission and an increase in evoked excitatory neurotransmission. (b) The overexpression of MeCP2 suppresses the expression of synaptic genes, which augments spontaneous excitatory transmission but decreases evoked release probability.