Impaired Subcortical Processing of Amplitude-Modulated Tones in Mice Deficient for Cacna2d3, a Risk Gene for Autism Spectrum Disorders in Humans
Impaired Subcortical Processing of Amplitude-Modulated Tones in Mice Deficient for Cacna2d3, a Risk Gene for Autism Spectrum Disorders in Humans
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DOI：
10.1523/eneuro.0118-22.2022
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发表时间：
2022-03-01
期刊：
影响因子：
3.4
通讯作者：
Kurt, Simone
中科院分区：
文献类型：
--
作者：
Bracic, Gerhard;Hegmann, Katrin;Kurt, Simone
复杂声音的时间处理是听觉中一项基本而复杂的任务，也是处理和理解发声、言语和韵律的先决条件。在这里，我们研究了缺乏Cacna 2d 3（自闭症谱系障碍（ASD）的风险基因）的小鼠下丘（IC）神经元的反应特性。由Cacna 2d 3编码的α（2）δ 3辅助性Ca 2+通道亚基对于听觉脑干中的突触的正常功能是必不可少的。最近的证据表明，许多听觉特征提取是在听觉脑干和IC中进行的，包括幅度调制（AM）的处理。我们确定了麻醉小鼠IC中单单位和多单位反应的光谱和时间特性。与α（2）δ 3（+/+）小鼠相比，α（2）δ 3（-/-）小鼠的IC单位显示出正常的调谐特性，但增加了自发频率。当用AM音刺激时，alpha（2）delta 3（-/-）单位表现出较不精确的时间编码，并降低了对较高调制频率（f（m））的诱发率。尽管第一尖峰潜伏期（FSL）仅在少数调制频率下增加，但在α（2）δ 3（-/-）IC单元中，在20至100 Hz范围内的fm下，群体峰值潜伏期增加。随着f（m）从70 Hz增加到160 Hz，时间编码的精度损失的特征在于使用归一化的偏移校正（Pearson样）相关系数，其看起来比矢量强度的度量更合适。在IC水平分析的AM声音的处理缺陷表明，α（2）δ 3（-/-）小鼠表现出皮层下听觉处理障碍（APD）。类似的缺陷可能存在于其他ASD小鼠模型中。
Temporal processing of complex sounds is a fundamental and complex task in hearing and a prerequisite for processing and understanding vocalization, speech, and prosody. Here, we studied response properties of neurons in the inferior colliculus (IC) in mice lacking Cacna2d3, a risk gene for autism spectrum disorders (ASDs). The alpha(2)delta 3 auxiliary Ca2+ channel subunit encoded by Cacna2d3 is essential for proper function of glutamatergic synapses in the auditory brainstem. Recent evidence has shown that much of auditory feature extraction is performed in the auditory brainstem and IC, including processing of amplitude modulation (AM). We determined both spectral and temporal properties of single- and multi-unit responses in the IC of anesthetized mice. IC units of alpha(2)delta 3(-/-) mice showed normal tuning properties yet increased spontaneous rates compared with alpha(2)delta 3(+/+). When stimulated with AM tones, alpha(2)delta 3(-/-) units exhibited less precise temporal coding and reduced evoked rates to higher modulation frequencies (f(m)). Whereas first spike latencies (FSLs) were increased for only few modulation frequencies, population peak latencies were increased for f m ranging from 20 to 100 Hz in alpha(2)delta 3(-/-) IC units. The loss of precision of temporal coding with increasing f(m) from 70 to 160 Hz was characterized using a normalized offset-corrected (Pearson-like) correlation coefficient, which appeared more appropriate than the metrics of vector strength. The processing deficits of AM sounds analyzed at the level of the IC indicate that alpha(2)delta 3(-/-) mice exhibit a subcortical auditory processing disorder (APD). Similar deficits may be present in other mouse models for ASDs.