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bioRxiv · 10.1101/2023.10.02.560501

Inhibitory synaptic transmission is impaired in the Kölliker-Fuse of male, but not female, Rett Syndrome Mice

Whitaker-Fornek, J. R.·Jenkins, P. M.·Levitt, E. S.
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Abstract

Rett Syndrome (RTT) is a severe neurodevelopmental disorder that mainly affects girls and women due to silencing mutations in the X-linked MECP2 gene. One of the most troubling symptoms of RTT is breathing irregularity, including apneas, breath-holds, and hyperventilation. Mice with silencing mutations in Mecp2 exhibit breathing abnormalities similar to human patients and serve as useful models for studying mechanisms underlying breathing problems in RTT. Previous work implicated the pontine, respiratory-controlling Kolliker-Fuse (KF) in the breathing problems in RTT. The goal of this study was to test the hypothesis that inhibitory synaptic transmission is deficient in KF neurons from symptomatic male and female RTT mice. We performed whole-cell voltage-clamp recordings from KF neurons in acute brain slices to examine pharmacologically isolated, spontaneous and electrically evoked inhibitory post-synaptic currents (IPSCs) in RTT mice and age- and sex-matched wild type mice. The frequency of spontaneous IPSCs was reduced in KF neurons from male RTT mice, but not female RTT mice. In addition, electrically evoked IPSCs were less reliable in KF neurons from male RTT mice, but not female RTT mice. KF neurons from male RTT mice were also more excitable and exhibited shorter duration action potentials. Increased excitability of KF neurons from male mice was not explained by changes in axon initial segment length. These findings indicate impaired inhibitory neurotransmission and increased excitability of KF neurons in male, but not female RTT mice, and suggest that sex-dependent mechanisms contribute to breathing problems in RTT. New and NoteworthyKolliker-Fuse (KF) neurons in acute brain slices from male Rett syndrome (RTT) mice receive reduced inhibitory synaptic inputs compared with wild type littermates. In female RTT mice, inhibitory transmission was not different in KF neurons compared with controls. The results from this study show that sex-specific alterations in synaptic transmission occur in the KF of RTT mice. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/560501v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@399b6forg.highwire.dtl.DTLVardef@bc5c3org.highwire.dtl.DTLVardef@e4b98corg.highwire.dtl.DTLVardef@519df7_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Whitaker-Fornek, J. R., Jenkins, P. M., Levitt, E. S.. 2023-10-02. Inhibitory synaptic transmission is impaired in the Kölliker-Fuse of male, but not female, Rett Syndrome Mice. https://doi.org/10.1101/2023.10.02.560501

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