Garcia-Pino Elisabet, Gessele Nikodemus, Koch Ursula
Institute of Biology, Neurophysiology, Freie Universität Berlin, 14195 Berlin, Germany, and.
Institute of Biology, Neurophysiology, Freie Universität Berlin, 14195 Berlin, Germany, and
J Neurosci. 2017 Aug 2;37(31):7403-7419. doi: 10.1523/JNEUROSCI.2310-16.2017. Epub 2017 Jul 3.
Hypersensitivity to sounds is one of the prevalent symptoms in individuals with Fragile X syndrome (FXS). It manifests behaviorally early during development and is often used as a landmark for treatment efficacy. However, the physiological mechanisms and circuit-level alterations underlying this aberrant behavior remain poorly understood. Using the mouse model of FXS (), we demonstrate that functional maturation of auditory brainstem synapses is impaired in FXS. KO mice showed a greatly enhanced excitatory synaptic input strength in neurons of the lateral superior olive (LSO), a prominent auditory brainstem nucleus, which integrates ipsilateral excitation and contralateral inhibition to compute interaural level differences. Conversely, the glycinergic, inhibitory input properties remained unaffected. The enhanced excitation was the result of an increased number of cochlear nucleus fibers converging onto one LSO neuron, without changing individual synapse properties. Concomitantly, immunolabeling of excitatory ending markers revealed an increase in the immunolabeled area, supporting abnormally elevated excitatory input numbers. Intrinsic firing properties were only slightly enhanced. In line with the disturbed development of LSO circuitry, auditory processing was also affected in adult KO mice as shown with single-unit recordings of LSO neurons. These processing deficits manifested as an increase in firing rate, a broadening of the frequency response area, and a shift in the interaural level difference function of LSO neurons. Our results suggest that this aberrant synaptic development of auditory brainstem circuits might be a major underlying cause of the auditory processing deficits in FXS. Fragile X Syndrome (FXS) is the most common inheritable form of intellectual impairment, including autism. A core symptom of FXS is extreme sensitivity to loud sounds. This is one reason why individuals with FXS tend to avoid social interactions, contributing to their isolation. Here, a mouse model of FXS was used to investigate the auditory brainstem where basic sound information is first processed. Loss of the Fragile X mental retardation protein leads to excessive excitatory compared with inhibitory inputs in neurons extracting information about sound levels. Functionally, this elevated excitation results in increased firing rates, and abnormal coding of frequency and binaural sound localization cues. Imbalanced early-stage sound level processing could partially explain the auditory processing deficits in FXS.
对声音过敏是脆性X综合征（FXS）患者中普遍存在的症状之一。它在发育早期就表现为行为症状，常被用作治疗效果的一个标志。然而，这种异常行为背后的生理机制和神经回路水平的改变仍知之甚少。利用FXS小鼠模型，我们证明了FXS中听觉脑干突触的功能成熟受到损害。敲除小鼠在外侧上橄榄核（LSO）神经元中表现出兴奋性突触输入强度大大增强，LSO是一个重要的听觉脑干核，它整合同侧兴奋和对侧抑制以计算双耳水平差异。相反，甘氨酸能抑制性输入特性未受影响。兴奋性增强是由于更多的耳蜗核纤维汇聚到一个LSO神经元上，而单个突触特性没有改变。同时，兴奋性终末标记物的免疫标记显示免疫标记面积增加，支持兴奋性输入数量异常增加。内在放电特性仅略有增强。与LSO神经回路发育紊乱一致，成年敲除小鼠的听觉处理也受到影响，如LSO神经元的单单元记录所示。这些处理缺陷表现为放电率增加、频率响应区域变宽以及LSO神经元的双耳水平差异功能发生偏移。我们的结果表明，听觉脑干回路这种异常的突触发育可能是FXS听觉处理缺陷的一个主要潜在原因。脆性X综合征（FXS）是最常见的遗传性智力障碍形式，包括自闭症。FXS的一个核心症状是对大声极度敏感。这就是为什么FXS患者倾向于避免社交互动，导致他们孤立的一个原因。在此，使用FXS小鼠模型来研究首先处理基本声音信息的听觉脑干。脆性X智力低下蛋白的缺失导致在提取声音水平信息的神经元中兴奋性输入与抑制性输入相比过多。在功能上，这种增强的兴奋性导致放电率增加，以及频率和双耳声音定位线索的异常编码。早期声音水平处理失衡可能部分解释了FXS中的听觉处理缺陷。
