Vascular smooth muscle TRPC3 channels facilitate the inverse hemodynamic response during status epilepticus
Vascular smooth muscle TRPC3 channels facilitate the inverse hemodynamic response during status epilepticus
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DOI：
10.1038/s41598-020-57733-0
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发表时间：
2020-01-21
影响因子：
4.6
通讯作者：
Zheng, Fang
中科院分区：
文献类型：
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作者：
Cozart, Michael A.;Phelan, Kevin D.;Zheng, Fang
人癫痫持续状态（SE）与病理性脑血流减少有关，称为逆血流动力学反应（IHR）。典型瞬时受体电位3 （TRPC3）通道是SE癫痫发作传播不可或缺的一部分，血管平滑肌细胞（VSMC） TRPC3通道参与血管收缩。因此，我们假设脑血管TRPC3通道可能与癫痫诱发的IHR有关。为了检验这种可能性，我们开发了一种平滑肌特异性TRPC3敲除（TRPC3smcKO）小鼠。为了量化神经血管耦合的变化，我们将激光散斑对比成像与同步脑电图记录相结合。对照小鼠表现出多重ihr，并且在SE期间脑血流量有限增加，且具有高度的瞬间变异性，其中血流量与神经元活动无关。相比之下，TRPC3smcKO小鼠的血流量增加幅度更大，变化较小，与神经元活动呈正相关。平滑肌TRPC3通道的基因消融通过消除第二阶段的剧烈癫痫发作缩短了SE的持续时间，这在同窝对照中是明显的。我们的结果与脑VSMCs表达的TRPC3通道参与SE期间的IHR的观点一致，这是SE进展的关键因素。
Human status epilepticus (SE) is associated with a pathological reduction in cerebral blood flow termed the inverse hemodynamic response (IHR). Canonical transient receptor potential 3 (TRPC3) channels are integral to the propagation of seizures in SE, and vascular smooth muscle cell (VSMC) TRPC3 channels participate in vasoconstriction. Therefore, we hypothesize that cerebrovascular TRPC3 channels may contribute to seizure-induced IHR. To examine this possibility, we developed a smooth muscle-specific TRPC3 knockout (TRPC3smcKO) mouse. To quantify changes in neurovascular coupling, we combined laser speckle contrast imaging with simultaneous electroencephalogram recordings. Control mice exhibited multiple IHRs, and a limited increase in cerebral blood flow during SE with a high degree of moment-to-moment variability in which blood flow was not correlated with neuronal activity. In contrast, TRPC3smcKO mice showed a greater increase in blood flow that was less variable and was positively correlated with neuronal activity. Genetic ablation of smooth muscle TRPC3 channels shortened the duration of SE by eliminating a secondary phase of intense seizures, which was evident in littermate controls. Our results are consistent with the idea that TRPC3 channels expressed by cerebral VSMCs contribute to the IHR during SE, which is a critical factor in the progression of SE.