Oginsky Max F, Cui Ningren, Zhong Weiwei, Johnson Christopher M, Jiang Chun
Department of Biology, Georgia State University, Atlanta, Georgia.
J Cell Physiol. 2017 May;232(5):1151-1164. doi: 10.1002/jcp.25589. Epub 2016 Sep 30.
People with Rett syndrome (RTT) have defects in motor function also seen in Mecp2-null mice. Motor function depends on not only central motor commands but also sensory feedback that is vulnerable to changes in excitability of propriosensory neurons. Here we report evidence for hyperexcitability of mesencephalic trigeminal (Me5) neurons in Mecp2-null mice and a novel cellular mechanism for lowering its impact. In in vitro brain slices, the Me5 neurons in both Mecp2 male and symptomatic Mecp2 female mice were overly excitable showing increased firing activity in comparison to their wild-type (WT) male and asymptomatic counterparts. In Mecp2 males, Me5 neurons showed a reduced firing threshold. Consistently, the steady-state activation of voltage-gated Na currents (I ) displayed a hyperpolarizing shift in the Mecp2-null neurons with no change in the I density. This seems to be due to NaV1.1, SCN1B and SCN4B overexpression and NaV1.2 and SCN3B under-expression. In contrast to the hyperexcitability, the sag potential and postinhibitory rebound (PIR) were reduced in Mecp2-null mice. In voltage-clamp, the I density was deficient by ∼33%, and the steady-state half-activation had a depolarizing shift of ∼10 mV in the Mecp2-null mice. Quantitative PCR analysis indicated that HCN2 was decreased, HCN1 was upregulated with no change in HCN4 in Mecp2 mice compared to WT. Lastly, blocking I reduced the firing rate much more in WT than in Mecp2-null neurons. These data suggest that the Mecp2 defect causes an increase in Me5 neuronal excitability likely attributable to alterations in I , meanwhile I is reduced likely altering neuronal excitability as well. J. Cell. Physiol. 232: 1151-1164, 2017. © 2016 Wiley Periodicals, Inc.
患有雷特综合征（RTT）的人存在运动功能缺陷，这在Mecp2基因敲除小鼠中也有体现。运动功能不仅取决于中枢运动指令，还依赖于感觉反馈，而感觉反馈容易受到本体感觉神经元兴奋性变化的影响。在此，我们报告了Mecp2基因敲除小鼠中脑三叉神经（Me5）神经元兴奋性过高的证据以及一种降低其影响的新细胞机制。在体外脑片中，Mecp2雄性小鼠和有症状的Mecp2雌性小鼠的Me5神经元兴奋性过高，与野生型（WT）雄性小鼠和无症状的对应小鼠相比，其放电活动增加。在Mecp2雄性小鼠中，Me5神经元的放电阈值降低。一致地，电压门控钠电流（I）的稳态激活在Mecp2基因敲除神经元中显示出超极化偏移，而I密度没有变化。这似乎是由于NaV1.1、SCN1B和SCN4B的过表达以及NaV1.2和SCN3B的低表达。与兴奋性过高相反，Mecp2基因敲除小鼠的下陷电位和抑制后反弹（PIR）降低。在电压钳实验中，Mecp2基因敲除小鼠的I密度不足约33%，稳态半激活有约10 mV的去极化偏移。定量PCR分析表明，与WT相比，Mecp2小鼠中HCN2减少，HCN1上调，HCN4无变化。最后，阻断I对WT神经元放电率的降低作用比对Mecp2基因敲除神经元的作用大得多。这些数据表明，Mecp2缺陷导致Me5神经元兴奋性增加，这可能归因于I 的改变，同时I 降低也可能改变神经元兴奋性。《细胞生理学杂志》2017年第232卷：1151 - 1164页。© 2016威利期刊公司
