Beebe K, Wang Y, Kulesza R
Lake Erie College of Osteopathic Medicine, Auditory Research Center, Erie, PA, USA.
Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle, WA, USA.
Neuroscience. 2014 Jul 25;273:79-91. doi: 10.1016/j.neuroscience.2014.05.006. Epub 2014 May 15.
Fragile X mental retardation protein (FMRP) binds select mRNAs, functions in intracellular transport of these mRNAs and represses their translation. FMRP is highly expressed in neurons and lack of FMRP has been shown to result in dendritic dysmorphology and altered synaptic function. FMRP is known to interact with mRNAs for the Kv3.1b potassium channel which is required for neurons to fire action potentials at high rates with remarkable temporal precision. Auditory brainstem neurons are known for remarkably high spike rates and expression of Kv3.1b potassium channels. Fragile X syndrome (FXS) is a genetic disorder caused by a mutation in the fragile X mental retardation 1 gene (Fmr1) resulting in decreased expression of FMRP and subsequent intellectual disability, seizures, attention deficit and hypersensitivity to auditory and other sensory stimuli. We therefore hypothesize that the auditory difficulties in FXS result, at least in part, from dysfunction of auditory brainstem neurons. To examine this hypothesis, we have studied normal human brainstem tissue with immunohistochemical techniques and confocal microscopy. Our results demonstrate that FMRP is widely expressed in cell bodies and dendritic arbors of neurons in the human cochlear nucleus and superior olivary complex and also that coincidence detector neurons of the medial superior olive colocalization of FMRP and Kv3.1b. We interpret these observations to suggest that the lower auditory brainstem is a potential site of dysfunction in FXS.
脆性X智力低下蛋白（FMRP）可结合特定的信使核糖核酸（mRNA），在这些mRNA的细胞内运输中发挥作用并抑制其翻译。FMRP在神经元中高度表达，并且已证明缺乏FMRP会导致树突形态异常和突触功能改变。已知FMRP与Kv3.1b钾通道的mRNA相互作用，而Kv3.1b钾通道是神经元以极高的时间精度高速激发动作电位所必需的。听觉脑干神经元以极高的放电率和Kv3.1b钾通道的表达而闻名。脆性X综合征（FXS）是一种由脆性X智力低下1基因（Fmr1）突变引起的遗传性疾病，导致FMRP表达降低，继而出现智力残疾、癫痫发作、注意力缺陷以及对听觉和其他感觉刺激的超敏反应。因此，我们推测FXS患者的听觉障碍至少部分是由听觉脑干神经元功能障碍所致。为了验证这一假设，我们运用免疫组织化学技术和共聚焦显微镜对正常人类脑干组织进行了研究。我们的结果表明，FMRP在人耳蜗核和上橄榄复合体神经元的细胞体和树突分支中广泛表达，并且在内侧上橄榄的重合检测神经元中FMRP与Kv3.1b共定位。我们对这些观察结果的解释是，听觉脑干下部是FXS中潜在的功能障碍部位。
