Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah 84108.
Interdepartmental Neuroscience Program, University of Utah School of Medicine, Salt Lake City, Utah 84108.
J Neurosci. 2022 Mar 16;42(11):2371-2383. doi: 10.1523/JNEUROSCI.2930-20.2021. Epub 2021 Dec 2.
Spreading depolarizations (SDs) of gray matter occur in the brain in different pathologic conditions, and cause varying degrees of tissue damage depending on the extent of metabolic burden on the tissue. As might be expected for such large depolarizations, neurons exhibit bursts of action potentials (APs) as the wave propagates. However, the specific role of APs in SD propagation is unclear. This is potentially consequential, since sodium channel modulation has not been considered as a therapeutic target for SD-associated disorders, because of ambiguous experimental evidence. Using whole-cell electrophysiology and single-photon imaging in acute cortical slices from male C57Bl6 mice, we tested the effects of AP blockade on SDs generated by two widely used induction paradigms. We found that AP blockade using tetrodotoxin (TTX) restricted propagation of focally induced SDs, and significantly reduced the amplitude of neuronal depolarization, as well as its Ca load. TTX also abolished the suppression of spontaneous synaptic activity that is a hallmark of focally induced SD. In contrast, TTX did not affect the propagation of SD induced by global superfusion of high [K] containing artificial CSF (ACSF). Thus, we show that voltage-gated sodium channel (Na)-mediated neuronal AP bursts are critical for the propagation and downstream effects of focally induced SD but are less important when the ionic balance of the extracellular space is already compromised. In doing so we corroborate the notion that two different SD induction paradigms, each relevant to different clinical situations, vary significantly in their characteristics and potentially their response to treatment. Our findings suggest that voltage-gated sodium channel (Na) channels have a critical role in the propagation and downstream neural effects of focally induced spreading depolarization (SD). As SDs are likely induced focally in many disease conditions, these studies support sodium channel modulation, a previously underappreciated therapeutic option in SD-associated disorders, as a viable approach.
灰质变薄（SDs）在不同的病理条件下发生在大脑中，并根据组织的代谢负担程度造成不同程度的组织损伤。由于如此大的去极化，神经元在波传播时会表现出动作电位（APs）的爆发。然而，AP 在 SD 传播中的具体作用尚不清楚。这可能是有后果的，因为由于实验证据不明确，钠通道调节尚未被认为是与 SD 相关疾病的治疗靶点。在来自雄性 C57Bl6 小鼠的急性皮质切片中使用全细胞电生理学和单光子成像，我们测试了 AP 阻断对两种广泛使用的诱导范式产生的 SD 的影响。我们发现，使用河豚毒素（TTX）阻断 AP 限制了局灶性诱导的 SD 的传播，并显著降低了神经元去极化的幅度及其 Ca 负荷。TTX 还消除了局灶性诱导 SD 的标志，即自发突触活动的抑制。相比之下，TTX 不影响由高 [K] 人工 CSF（ACSF）全灌流诱导的 SD 的传播。因此，我们表明，电压门控钠通道（Na）介导的神经元 AP 爆发对于局灶性诱导的 SD 的传播和下游效应至关重要，但在细胞外空间的离子平衡已经受损时则不太重要。这样做我们证实了这样一种观点，即两种不同的 SD 诱导范式，每种范式都与不同的临床情况相关，在其特征上存在显著差异，并且可能对治疗的反应也存在差异。我们的发现表明，电压门控钠通道（Na）通道在局灶性诱导的 SD 的传播和下游神经效应中具有关键作用。由于 SD 在许多疾病情况下可能是局灶性诱导的，因此这些研究支持钠通道调节，这是一种以前被低估的 SD 相关疾病的治疗选择，作为一种可行的方法。
