Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom.
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8720-5. doi: 10.1073/pnas.1219578110. Epub 2013 May 6.
The development of neural circuits relies on spontaneous electrical activity that occurs during immature stages of development. In the developing mammalian auditory system, spontaneous calcium action potentials are generated by inner hair cells (IHCs), which form the primary sensory synapse. It remains unknown whether this electrical activity is required for the functional maturation of the auditory system. We found that sensory-independent electrical activity controls synaptic maturation in IHCs. We used a mouse model in which the potassium channel SK2 is normally overexpressed, but can be modulated in vivo using doxycycline. SK2 overexpression affected the frequency and duration of spontaneous action potentials, which prevented the development of the Ca(2+)-sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their morphology or general cell development. By manipulating the in vivo expression of SK2 channels, we identified the "critical period" during which spiking activity influences IHC synaptic maturation. Here we provide direct evidence that IHC development depends upon a specific temporal pattern of calcium spikes before sound-driven neuronal activity.
神经回路的发育依赖于发育早期自发的电活动。在发育中的哺乳动物听觉系统中，内毛细胞（IHC）产生自发的钙动作电位，形成主要的感觉突触。目前尚不清楚这种电活动是否是听觉系统功能成熟所必需的。我们发现，与感觉无关的电活动控制着 IHC 中的突触成熟。我们使用了一种小鼠模型，其中钾通道 SK2 通常过表达，但可以使用强力霉素在体内进行调节。SK2 的过表达影响自发动作电位的频率和持续时间，这阻止了 IHC 带突触融合的 Ca（2+）敏感性的发展，而不影响其形态或一般细胞发育。通过操纵 SK2 通道的体内表达，我们确定了在声音驱动的神经元活动之前影响 IHC 突触成熟的“关键期”。在这里，我们提供了直接的证据，证明 IHC 的发育取决于钙峰的特定时间模式，而不是声音驱动的神经元活动。
