缺乏GABAB受体辅助亚基KCTD12的小鼠表现出听觉增益增强和类耳鸣行为

文献信息

中文摘要

背景： 神经增益的精确调控对于准确的感觉处理至关重要，并依赖于限制神经元反应性的抑制性机制。抑制性控制的破坏已被认为与包括耳鸣在内的感觉知觉异常疾病有关，但调节抑制性信号传导的分子机制仍知之甚少。方法：在此，我们使用KCTD12缺陷小鼠研究了含钾通道四聚化结构域蛋白12（KCTD12）——γ-氨基丁酸B型受体（GABABR）的辅助亚基，也是慢性耳鸣的候选风险修饰因子——在听觉回路功能中的作用。结果：尽管KCTD12在耳蜗中大量表达，但Kctd12的缺失并未影响耳蜗内电位、外毛细胞功能或听阈，表明外周听觉敏感性得以保留。相比之下，KCTD12缺陷小鼠表现出阈上听觉反应增强、声惊跳反应性增加以及声惊跳的间隙前脉冲抑制缺陷，这与听觉增益改变和类耳鸣行为一致。下丘的电生理记录显示自发活动增加、声诱发反应增强以及速率-水平函数更陡峭，表明中枢听觉反应性升高。在背侧耳蜗核内，KCTD12选择性表达于抑制性轮状细胞，其缺失降低了GABABR表达和巴氯芬诱发反应，而兴奋性梭形神经元基本不受影响。结论：这些发现将KCTD12确定为GABABR介导抑制的细胞类型特异性调节因子，并证明其缺失会增加中枢听觉回路中的神经增益并产生类耳鸣行为。

英文摘要

Precise regulation of neural gain is essential for accurate sensory processing and relies on inhibitory mechanisms that constrain neuronal responsiveness. Disruption of inhibitory control has been implicated in disorders characterized by abnormal sensory perception, including tinnitus, yet the molecular mechanisms regulating inhibitory signaling remain poorly understood. Here, we investigated the role of potassium channel tetramerization domain-containing protein 12 (KCTD12)-an auxiliary subunit of the γ-aminobutyric acid type B receptor (GABABR) and a proposed risk modifier for chronic tinnitus-in auditory circuit function using KCTD12-deficient mice. Despite abundant KCTD12 expression in the cochlea, deletion of Kctd12 did not affect endocochlear potential, outer hair cell function, or auditory thresholds, demonstrating preserved peripheral auditory sensitivity. In contrast, KCTD12-deficient mice displayed enhanced suprathreshold auditory responses, increased acoustic startle reactivity, and deficits in gap-prepulse inhibition of acoustic startle, consistent with altered auditory gain and tinnitus-like behavior. Electrophysiological recordings from the inferior colliculus revealed increased spontaneous activity, enhanced sound-evoked responses, and steeper rate-level functions, indicating elevated central auditory responsiveness. Within the dorsal cochlear nucleus, KCTD12 was selectively expressed in inhibitory cartwheel cells, where its loss reduced GABABR expression and baclofen-evoked responses, while excitatory fusiform neurons were largely unaffected. These findings identify KCTD12 as a cell-type-specific modulator of GABABR-mediated inhibition and demonstrate that its loss increases neural gain in central auditory circuits and produces tinnitus-like behavior.