Rett syndrome (RTT) is a neurodevelopmental disorder with symptoms starting 6-18 months after birth, while what underlies the delayed onset is unclear. Allopregnanolone (Allop) is a metabolite of progesterone, and a potent modulator of GABA_A-ergic currents whose defects are seen in RTT. Allop changes its concentrations during the perinatal period, which may affect central neurons via the GABA_A-ergic synaptic transmission, contributing to the onset of the disease. To determine whether the Mecp2 disruption affects the Allop modulation, we performed the studies in brain slices obtained from wild-type (WT) and Mecp2^–/Y mice. Allop dose-dependently suppressed locus coeruleus (LC) neuronal excitability in WT mice, while the Mecp2-null neurons showed significant defects. Using optogenetic approaches, channelrhodopsin was specifically expressed in GABA-ergic neurons in which optical stimulation evoked action potentials. In LC neurons of WT mice, Allop exposure increased the amplitude of GABA_A-ergic inhibitory postsynaptic currents (IPSCs) evoked by optical stimulation, and prolonged the IPSC decay time. Consistently, Allop augmented both frequency and amplitude of GABAA-ergic spontaneous IPSCs (sIPSCs), and expended the sIPSC decay time. The Allop-induced potentiation of sIPSCs was deficient in Mecp2^–/Y mice. Surprisingly, the impairment occurred at 3 weeks of the postnatal age, while no significant difference in the Allop modulation was observed in 1-2 weeks between the WT and Mecp2^–/Y mice. These results indicate that the modulation of GABAA-ergic synaptic transmission by Allop is impaired in LC neurons of Mecp2-null mice at a time when RTT-like symptoms manifest, suggesting a potential mechanism for the delayed onset of the disease.