Time-dependent modulation of GABA(A)-ergic synaptic transmission by allopregnanolone in locus coeruleus neurons of Mecp2-null mice.
Rett syndrome (RTT) is a neurodevelopmental disorder with symptoms starting 6-18 mo after birth, while what underlies the delayed onset is unclear. Allopregnanolone (Allop) is a metabolite of progesterone and a potent modulator of GABAA-ergic currents whose defects are seen in RTT. Allop changes its concentration during the perinatal period, which may affect central neurons via the GABAA-ergic synaptic transmission, contributing to the onset of the disease. To determine whether Mecp2 disruption affects Allop modulation, we performed 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 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 GABAA-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 extended the decay time of sIPSCs. The Allop-induced potentiation of sIPSCs was deficient in Mecp2(-/Y) mice. Surprisingly, the impairment occurred at 3 wk postnatal age, while no significant difference in Allop modulation was observed in 1-2 wk between 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.
Department of Biology, Georgia State University, Atlanta, Georgia.
Xin
X
Jin
Weiwei
W
Zhong
Chun
C
Jiang
D000818:Animals; D059330:GABAergic Neurons / Q000187:drug effects / Q000473:pathology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009924:Organ Culture Techniques; D011280:Pregnanolone / Q000494:pharmacology*; D015518:Rett Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D011280:Pregnanolone
GABAA-ergic; Rett syndrome; allopregnanolone; development; locus coeruleus