Rett syndrome (RTT) is associated with mutations in the transcriptional 
repressor gene MeCP2. Although the clinical and neuropathological signs of RTT 
suggest disrupted synaptic function, the specific role of methyl-CpG binding 
protein 2 (MeCP2) in postmitotic neurons remains relatively unknown. We examined 
whether MeCP2 deficiency in central neurons contributes to the neuropathogenesis 
in RTT. Primary cerebellar granule neuronal cultures from wild-type (WT) and 
MeCP2-/- mice were exposed to N-methyl-d-aspartate (NMDA) and AMPA-induced 
excitotoxicity and hypoxic-ischemic insult. The magnitude of cell death in 
MeCP2-/- cells after excitotoxicity and hypoxia was greater than in the WT 
littermate control cultures and occurred after shorter exposures that usually, 
in the WT, would not cause cell death. Pretreatment with the growth factor 
fibroblast growth factor 1 (FGF-1) under conditions at which WT cells showed 
complete neuroprotection, only partially protected MeCP2-/- cells. To elucidate 
specifically the effects of MeCP2 knockout (KO) on cell death, we examined two 
death cascade pathways. MeCP2-/- neurons exposed to 6 h of hypoxia exhibited 
enhanced activation of the proapoptotic caspase-3 and increased mitochondrial 
release of apoptosis inducing factor (AIF) compared with WT neurons, which did 
not show significant changes. However, pretreatment with the caspase inhibitor 
ZVAD-FMK had little or no effect on AIF release and its subcellular 
translocation to the nucleus, suggesting caspase-independent AIF release and 
their independent contribution to hypoxia-induced cell death. Reintroduction of 
intact MeCP2 gene in MeCP2-/- cells or MeCP2 gene silencing by MeCP2siRNA in WT 
cells further confirmed the differential sensitivity of the WT and MeCP2-/- 
cells and suggest a direct role of MeCP2 in cell death. These results clearly 
demonstrate increased cell death occurred in neurons lacking MeCP2 expression 
via both caspase- and AIF-dependent apoptotic mechanisms. Our findings suggest a 
novel, yet unknown, role for MeCP2 in central neurons in the control of neuronal 
response to cell death.