PDF(Pubmed)
Abstract：
Parvalbumin-expressing interneurons (PVINs) play a crucial role within the dorsal horn of the spinal cord by preventing touch inputs from activating pain circuits. In both male and female mice, nerve injury decreases PVINs\' output via mechanisms that are not fully understood. In this study, we show that PVINs from nerve-injured male mice change their firing pattern from tonic to adaptive. To examine the ionic mechanisms responsible for this decreased output, we used a reparametrized Hodgkin-Huxley type model of PVINs, which predicted (1) the firing pattern transition is because of an increased contribution of small conductance calcium-activated potassium (SK) channels, enabled by (2) impairment in intracellular calcium buffering systems. Analyzing the dynamics of the Hodgkin-Huxley type model further demonstrated that a generalized Hopf bifurcation differentiates the two types of state transitions observed in the transient firing of PVINs. Importantly, this predicted mechanism holds true when we embed the PVIN model within the neuronal circuit model of the spinal dorsal horn. To experimentally validate this hypothesized mechanism, we used pharmacological modulators of SK channels and demonstrated that (1) tonic firing PVINs from naive male mice become adaptive when exposed to an SK channel activator, and (2) adapting PVINs from nerve-injured male mice return to tonic firing on SK channel blockade. Our work provides important insights into the cellular mechanism underlying the decreased output of PVINs in the spinal dorsal horn after nerve injury and highlights potential pharmacological targets for new and effective treatment approaches to neuropathic pain.SIGNIFICANCE STATEMENT Parvalbumin-expressing interneurons (PVINs) exert crucial inhibitory control over Aβ fiber-mediated nociceptive pathways at the spinal dorsal horn. The loss of their inhibitory tone leads to neuropathic symptoms, such as mechanical allodynia, via mechanisms that are not fully understood. This study identifies the reduced intrinsic excitability of PVINs as a potential cause for their decreased inhibitory output in nerve-injured condition. Combining computational and experimental approaches, we predict a calcium-dependent mechanism that modulates PVINs\' electrical activity following nerve injury: a depletion of cytosolic calcium buffer allows for the rapid accumulation of intracellular calcium through the active membranes, which in turn potentiates SK channels and impedes spike generation. Our results therefore pinpoint SK channels as potential therapeutic targets for treating neuropathic symptoms.
摘要：
表达小白蛋白的中间神经元（PVIN）通过防止触摸输入激活疼痛回路在脊髓背角中起关键作用。在雄性和雌性小鼠中，神经损伤通过尚未完全了解的机制减少PVIN的输出。在这项研究中,我们表明，来自神经损伤的雄性小鼠的PVIN改变了它们的放电模式，从补品到适应性。为了检查导致产量下降的离子机制，我们采用了重新参数化的Hodgkin-Huxley（HH）型PVIN模型，预测（1）点火模式转变是由于小电导钙激活钾（SK）通道的贡献增加，通过(2)细胞内钙缓冲系统的损伤。分析HH型模型的动力学进一步表明，广义Hopf分叉区分了PVIN瞬态激发中观察到的两种状态转变。重要的是,当我们将PVINs模型嵌入脊髓背角的神经元回路模型中时,这种预测的机制成立.为了实验验证这个假设的机制，我们使用了SK通道的药理学调节剂，并证明（1）当暴露于SK通道激活剂时，来自幼稚雄性小鼠的强直放电PVIN变得适应性。和（2）适应神经损伤的雄性小鼠的PVIN在SK通道阻断后恢复到强直放电。我们的工作为神经损伤后脊髓背角PVIN输出减少的细胞机制提供了重要见解，并强调了神经性疼痛新的有效治疗方法的潜在药理靶点。重要声明：表达小白蛋白的中间神经元（PVIN）对脊髓背角的Aβ纤维介导的伤害性途径具有关键的抑制控制作用。它们抑制音调的丧失会导致神经性症状，比如机械性异常性疼痛,通过尚未完全理解的机制。这项研究确定了PVIN的内在兴奋性降低是其在神经损伤状况下抑制输出降低的潜在原因。结合计算和实验方法，我们预测在神经损伤后调节PVINs电活动的钙依赖性机制：胞浆钙缓冲液的消耗允许细胞内钙通过活性膜的快速积累，这反过来增强SK通道并阻碍尖峰产生。因此，我们的结果将SK通道确定为治疗神经性症状的潜在治疗靶标。
