Wang Tiantian, van Woerden Geeske M, Elgersma Ype, Borst J Gerard G
Department of Neuroscience, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
Front Cell Neurosci. 2018 Jan 4;11:418. doi: 10.3389/fncel.2017.00418. eCollection 2017.
The neurodevelopmental disorder Angelman syndrome (AS) is characterized by intellectual disability, motor dysfunction, distinct behavioral aspects, and epilepsy. AS is caused by a loss of the maternally expressed gene, and many of the symptoms are recapitulated in a mouse model of this syndrome. At the cellular level, changes in the axon initial segment (AIS) have been reported, and changes in vesicle cycling have indicated the presence of presynaptic deficits. Here we studied the role of UBE3A in the auditory system by recording synaptic transmission at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) through whole cell and juxtacellular recordings. We show that MNTB principal neurons in mice exhibit a hyperpolarized resting membrane potential, an increased action potential (AP) amplitude and a decreased AP half width. Moreover, both the pre- and postsynaptic AP in the calyx of Held synapse of mice showed significantly faster recovery from spike depression. An increase in AIS length was observed in the principal MNTB neurons of mice, providing a possible substrate for these gain-of-function changes. Apart from the effect on APs, we also observed that EPSPs showed decreased short-term synaptic depression (STD) during long sound stimulations in AS mice, and faster recovery from STD following these tones, which is suggestive of a presynaptic gain-of-function. Our findings thus provide evidence that UBE3A plays a critical role in controlling synaptic transmission and excitability at excitatory synapses.
神经发育障碍天使综合征（AS）的特征是智力残疾、运动功能障碍、独特的行为表现和癫痫。AS是由母源表达基因的缺失引起的，该综合征的许多症状在小鼠模型中得以重现。在细胞水平上，已有报道轴突起始段（AIS）发生变化，囊泡循环的改变表明存在突触前缺陷。在这里，我们通过全细胞记录和近细胞记录，在梯形体内侧核（MNTB）的Held束突触处记录突触传递，研究了UBE3A在听觉系统中的作用。我们发现，AS小鼠MNTB主神经元表现出超极化的静息膜电位、动作电位（AP）幅度增加和AP半宽度减小。此外，AS小鼠Held束突触的突触前和突触后AP从峰电位抑制中恢复的速度明显更快。在AS小鼠的MNTB主神经元中观察到AIS长度增加，为这些功能增强变化提供了可能的基础。除了对AP的影响外，我们还观察到，在长时间声音刺激期间，AS小鼠的兴奋性突触后电位（EPSP）表现出短期突触抑制（STD）降低，并且在这些音调刺激后从STD中恢复得更快，这提示突触前功能增强。因此，我们的研究结果提供了证据，表明UBE3A在控制兴奋性突触的突触传递和兴奋性方面起着关键作用。
