The role of ion channels in shaping the function of inner ear neurons

摘要 前庭和听觉传入神经元是信息传递的主要通道 脑干的感觉外周。许多听力和平衡障碍是由 这些神经元或其配对毛细胞的死亡或损伤。在前庭和听觉上 传入某些功能不同的神经元亚群比 其他。通过了解塑造这些感觉神经元功能的机制， 我们希望更好地理解为什么会出现这种情况。我们假设地球上的异质性 神经元离子通道的组成对其功能的形成很重要。我们的基础是 前庭和听觉传入细胞胞体观察到的假说 在其固有的激发模式和离子通道上具有显著的异质性。以前的研究 不能可靠地将离子通道属性与传入功能联系起来，因为分离的细胞体 缺乏必要的形态标记来进行功能鉴定。去做交易 有了这个问题，我们将一起执行膜片钳记录和单细胞标记 半完整的神经上皮制剂，其中神经元仍与毛细胞相连。 我们将通过利用已建立的关联将离子通道属性与神经元功能联系起来 毛细胞的传入连接的功能和模式之间的关系。与 候选离子通道的药理学操作和理论模型，OUR 实验将测试特定的离子通道组是否以及如何影响神经元功能。 或者，该方法将提供新的候选离子通道供考虑。这些 实验还将有助于我们理解通过映射离子来实现神经元分化。 在关键发育期传入时通道特性对传入连接的影响 神经支配模式正在形成和稳定。通过采取发展的方式，我们将 解开离子通道多样性作为神经元成熟指标的意义 与其对成人功能的重要性相比。我们对前庭和听觉传入的关注 一项使用类似方法的研究将揭示离子通道的专门化 每个系统和两个系统通用的专业化认证。在定义离子如何 不同功能的神经元组之间的经络不同，我们的工作可能会识别 使一些神经元更容易受到损害的机制，这可能导致 保护脆弱神经元组的药理学干预。

SUMMARY Vestibular and auditory afferent neurons are the primary conduits for information transfer from the sensory periphery to the brainstem. Many hearing and balance impairments are caused by death or damage to these neurons or their partner hair cells. In both vestibular and auditory afferents some functionally distinct neuronal sub-groups are more susceptible to damage than others. By understanding the mechanisms that shape the function of these sensory neurons, we hope to better understand why this is the case. We hypothesize that heterogeneity in the composition of neuronal ion channels is important for shaping their function. We base our hypothesis on the observation that the cell bodies of vestibular and auditory afferents are remarkably heterogeneous in their intrinsic firing patterns and ion channels. Previous studies could not reliably link ion channel properties to afferent function because the isolated cell bodies lacked the necessary morphological markers that would allow functional identification. To deal with this problem, we will perform patch-clamp recordings together with single cell labeling in semi-intact neuro-epithelium preparations in which neurons are still connected to their hair cells. We will link ion channel properties with neuronal function by exploiting established associations between function and patterns of afferent connectivity with hair cells. Combined with pharmacological manipulation of candidate ion channels and theoretical modeling, our experiments will test if and how specific groups of ion channels influence neuronal function. Alternatively, the approach will offer new candidate ion channels for consideration. These experiments will also contribute to our understanding of neuronal differentiation by mapping ion channel properties onto afferent connectivity during critical developmental periods when afferent innervation patterns are forming and stabilizing. By taking a developmental approach we will disentangle the significance of ion channel diversity as an indication of neuronal maturation versus its importance for adult function. Our focus on vestibular and auditory afferents within one study, using similar methodology, will reveal ion channel specializations that are unique to each system and specializations that are common across both systems. In defining how ion channels differ among functionally distinct neuronal groups, our work may identify the mechanisms that render some neurons more susceptible to damage, which could lead to pharmacological interventions for protecting vulnerable neuronal groups.