IBME, University of Toronto, 164 College Street, Rosebrugh Building, Room 407, Toronto, ON M5S 3G9, Canada.
Krembil Research Institute, University Health Network, 135 Nassau Street, Toronto, ON M5T 1M8, Canada.
Int J Mol Sci. 2020 Oct 12;21(20):7510. doi: 10.3390/ijms21207510.
Pannexin-1 (Panx1) is suspected of having a critical role in modulating neuronal excitability and acute neurological insults. Herein, we assess the changes in behavioral and electrophysiological markers of excitability associated with Panx1 via three distinct models of epilepsy. Methods Control and Panx1 knockout C57Bl/6 mice of both sexes were monitored for their behavioral and electrographic responses to seizure-generating stimuli in three epilepsy models-(1) systemic injection of pentylenetetrazol, (2) acute electrical kindling of the hippocampus and (3) neocortical slice exposure to 4-aminopyridine. Phase-amplitude cross-frequency coupling was used to assess changes in an epileptogenic state resulting from Panx1 deletion.
Seizure activity was suppressed in Panx1 knockouts and by application of Panx1 channel blockers, Brilliant Blue-FCF and probenecid, across all epilepsy models. In response to pentylenetetrazol, WT mice spent a greater proportion of time experiencing severe (stage 6) seizures as compared to Panx1-deficient mice. Following electrical stimulation of the hippocampal CA3 region, Panx1 knockouts had significantly shorter evoked afterdischarges and were resistant to kindling. In response to 4-aminopyridine, neocortical field recordings in slices of Panx1 knockout mice showed reduced instances of electrographic seizure-like events. Cross-frequency coupling analysis of these field potentials highlighted a reduced coupling of excitatory delta-gamma and delta-HF rhythms in the Panx1 knockout.
These results suggest that Panx1 plays a pivotal role in maintaining neuronal hyperexcitability in epilepsy models and that genetic or pharmacological targeting of Panx1 has anti-convulsant effects.
连接蛋白 1（Panx1）被怀疑在调节神经元兴奋性和急性神经损伤方面发挥关键作用。在此，我们通过三种不同的癫痫模型评估与 Panx1 相关的兴奋性的行为和电生理标志物的变化。
监测雄性和雌性对照和 Panx1 敲除 C57Bl/6 小鼠对致痫刺激的行为和脑电图反应，这些刺激来自三种癫痫模型：（1）戊四氮全身注射，（2）海马急性电点燃和（3）皮质切片暴露于 4-氨基吡啶。相位-幅度交叉频率耦合用于评估 Panx1 缺失导致的癫痫状态变化。
在所有癫痫模型中，Panx1 敲除和 Panx1 通道阻滞剂 Brilliant Blue-FCF 和丙磺舒的应用均抑制了癫痫发作活动。与 Panx1 缺陷型小鼠相比，WT 小鼠在戊四氮处理后，经历严重（第 6 期）癫痫发作的比例更高。在海马 CA3 区电刺激后，Panx1 敲除小鼠的诱发后放电明显缩短，并且不易点燃。在 4-氨基吡啶反应中，Panx1 敲除型小鼠皮质切片的场记录显示电癫痫样事件的发生率降低。这些场电位的频域耦合分析突出了 Panx1 敲除型中兴奋性 δ-γ和 δ-HF 节律的耦合减少。
这些结果表明，Panx1 在维持癫痫模型中的神经元过度兴奋性方面发挥关键作用，并且 Panx1 的遗传或药理学靶向具有抗惊厥作用。
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