Dept. of Biology, University of Victoria, Victoria, BC, Canada V8W2Y2.
Dept. of Biology, University of Victoria, Victoria, BC, Canada V8W2Y2.
Neuroscience. 2019 Aug 21;414:141-153. doi: 10.1016/j.neuroscience.2019.07.008. Epub 2019 Jul 9.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene. Random X-inactivation produces a mosaic of mutant (MT) and wild-type (WT) neurons in female Mecp2+/- (het) mice. Many RTT symptoms are alleviated by increasing activity in medial prefrontal cortex (mPFC) in RTT model mice (Howell et al., 2017). Using a GFP-MeCP2 fusion protein to distinguish WT from MT pyramidal neurons in mPFC we found cell autonomous (cell genotype specific) and non-autonomous effects of MeCP2 deficiency on spontaneous excitatory/inhibitory balance, nicotinic acetylcholine receptor (nAChR) currents and evoked activity. MT Layer 5 and 6 (L5, L6) neurons of male nulls, and MT L6 of het mice had reduced spontaneous excitatory synaptic input compared to WT in wild-type male (WTm), female (WTf) and het mice. Inhibitory synaptic charge in MT L6 equaled WT in 2-4-month hets. At 6-7 months inhibitory charge in WT in het slices was increased compared to both MT in het and WT in WTf; however, in hets the excitatory/inhibitory charge ratio was still greater in WT compared to MT. nAChR currents were reduced in L6 of nulls and MT L6 in het slices compared to WT neurons of het, WTm and WTf. At 2-4 months, ACh perfusion increased frequency of inhibitory currents to L6 neurons equally in all genotypes but increased excitatory inputs to MT and WT in hets less than WT in WTfs. Unexpectedly ACh perfusion evoked greater sustained IPSC and EPSC input to L5 neurons of nulls compared to WTm.
雷特综合征（RTT）是一种由 X 连锁 MECP2 基因突变引起的神经发育障碍。随机的 X 染色体失活会在雌性 Mecp2+/-（杂合子）小鼠中产生突变型（MT）和野生型（WT）神经元的嵌合体。在 RTT 模型小鼠中，增加内侧前额叶皮层（mPFC）的活动可以缓解许多 RTT 症状（Howell 等人，2017 年）。我们使用 GFP-MeCP2 融合蛋白来区分 mPFC 中的 WT 和 MT 锥体神经元，发现 MeCP2 缺乏对自发性兴奋性/抑制性平衡、烟碱型乙酰胆碱受体（nAChR）电流和诱发活性具有细胞自主（细胞基因型特异性）和非自主效应。与 WT 相比，雄性 null 雄性、WTf 和 het 雌性小鼠的 MT 层 5 和 6（L5、L6）神经元的自发性兴奋性突触输入减少，而 2-4 月龄的 het 中的 MT L6 抑制性突触电荷与 WT 相等。在 6-7 月龄时，het 切片中 WT 的抑制性电荷与 MT 相比增加，而 WTf 中的 WT 则增加；然而，het 中的兴奋性/抑制性电荷比仍然大于 MT。与 WT 神经元相比，nulls 的 L6 和 het 切片中的 MT L6 的 nAChR 电流减少。在 2-4 个月时，ACh 灌注同样增加了所有基因型 L6 神经元抑制性电流的频率，但与 WTf 相比，het 中的兴奋性输入增加较少。出乎意料的是，ACh 灌注引起 nulls 的 L5 神经元产生更大的持续 IPSC 和 EPSC 输入，与 WTm 相比。
