Table_1_Effects of transient, persistent, and resurgent sodium currents on excitability and spike regularity in vestibular ganglion neurons.pdf

Vestibular afferent neurons occur as two populations with differences in spike timing regularity that are independent of rate. The more excitable regular afferents have lower current thresholds and sustained spiking responses to injected currents, while irregular afferent neurons have higher thresholds and transient responses. Differences in expression of low-voltage-activated potassium (KLV) channels are emphasized in models of spiking regularity and excitability in these neurons, leaving open the potential contributions of the voltage-gated sodium (NaV) channels responsible for the spike upstroke. We investigated the impact of different NaV current modes (transient, persistent, and resurgent) with whole-cell patch clamp experiments in mouse vestibular ganglion neurons (VGNs), the cultured and dissociated cell bodies of afferents. All VGNs had transient NaV current, many had a small persistent (non-inactivating) NaV current, and a few had resurgent current, which flows after the spike when NaV channels that were blocked are unblocked. A known NaV1.6 channel blocker decreased spike rate and altered spike waveforms in both sustained and transient VGNs and affected all three modes of NaV current. A NaV channel agonist enhanced persistent current and increased spike rate and regularity. We hypothesized that persistent and resurgent currents have different effects on sustained (regular) VGNs vs. transient (irregular) VGNs. Lacking blockers specific for the different current modes, we used modeling to isolate their effects on spiking of simulated transient and sustained VGNs, driven by simulated current steps and noisy trains of simulated EPSCs. In all simulated neurons, increasing transient NaV current increased spike rate and rate-independent regularity. In simulated sustained VGNs, adding persistent current increased both rate and rate-independent regularity, while adding resurgent current had limited impact. In transient VGNs, adding persistent current had little impact, while adding resurgent current increased both rate and rate-independent irregularity by enhancing sensitivity to synaptic noise. These experiments show that the small NaV current modes may enhance the differentiation of afferent populations, with persistent currents selectively making regular afferents more regular and resurgent currents selectively making irregular afferents more irregular.

前庭传入神经元（Vestibular afferent neurons）可分为两个群体，二者在锋电位时序规则性上存在差异，且该差异与放电频率无关。兴奋性更高的规则型传入神经元具有更低的电流阈值，对注入电流可产生持续锋电位响应；而不规则型传入神经元则具有更高的阈值，仅产生瞬态锋电位响应。现有关于此类神经元锋电位规则性与兴奋性的模型中，重点关注了低电压激活钾离子（KLV）通道的表达差异，而对于介导锋电位上升支的电压门控钠离子（NaV）通道的潜在贡献尚未明确。本研究通过对体外培养并解离的小鼠前庭神经节神经元（VGNs，即传入神经元的胞体）开展全细胞膜片钳实验，探究了不同NaV电流模式（瞬态、持续性及复发性）的影响。所有VGNs均表达瞬态NaV电流，多数神经元存在微弱的持续性（非失活型）NaV电流，少数神经元则表现出复发性NaV电流——该电流产生于锋电位结束后，此时先前被阻断的NaV通道恢复开放。一种已被证实的NaV1.6通道阻断剂可降低两类VGNs的放电频率并改变其锋电位波形，同时对上述三种NaV电流模式均产生影响。NaV通道激动剂则可增强持续性电流，提升放电频率与规则性。我们提出假说：持续性与复发性电流对持续放电型（规则型）VGNs与瞬态放电型（不规则型）VGNs的作用存在差异。由于缺乏针对不同电流模式的特异性阻断剂，我们采用建模手段，分离其对模拟的瞬态与持续放电型VGNs锋电位活动的影响，模拟刺激包括电流阶跃与带噪声的模拟兴奋性突触后电流（EPSCs）序列。在所有模拟神经元中，增大瞬态NaV电流可提升放电频率及与频率无关的规则性。在模拟的持续放电型VGNs中，引入持续性电流可同时提升放电频率与频率无关的规则性，而引入复发性电流则影响有限。在模拟的瞬态放电型VGNs中，引入持续性电流几乎无影响，而引入复发性电流则通过增强对突触噪声的敏感性，同时提升放电频率与频率无关的不规则性。本实验结果表明，微量的NaV电流模式可强化传入神经元群体的分化：持续性电流可选择性地使规则型传入神经元的放电更趋规则，而复发性电流则选择性地使不规则型传入神经元的放电更趋不规则。