Three principle observations emerge from our work: 1) changes in mean excitatory drive within the hippocampal network are not necessarily a critical component of these network alterations, 2) decreased excitatory fluctuations can be a critical factor in changes in hippocampal network oscillations in Rett syndrome, and 3) these fluctuations in excitatory levels can also explain hyper-excitable responses in MeCP2-deficient hippocampal networks. The gene discussed is MECP2; the disease is Rett syndrome.