Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability
Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability
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DOI：
10.1523/eneuro.0229-18.2019
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发表时间：
2019-11-01
期刊：
影响因子：
3.4
通讯作者：
Godwin, D. W.
中科院分区：
文献类型：
--
作者：
Klorig, D. C.;Alberto, G. E.;Godwin, D. W.
网络兴奋性受突触效能、内在兴奋性和表达这些因子的回路控制。这些因素之间复杂的相互作用决定了回路的功能，在极端情况下，决定了它们对癫痫发作的敏感性。我们已经开发了一个敏感的，定量的估计网络兴奋性在自由行为的小鼠使用一种新的光遗传强度响应程序。深层CA 1锥体细胞的同步激活产生异常的全网络癫痫样群体放电（PD），几乎无法区分自发发生的发作间期棘波（IIS）。通过系统地改变光强度，从而改变光遗传学介导的电流的大小，我们使用PD的概率作为因变量生成了强度响应曲线。已知增加兴奋性的操作，如化学惊厥剂戊四氮（PTZ）的亚惊厥剂量（20 mg/kg），与基线相比，曲线发生了显著变化。抗癫痫药物左乙拉西坦（LEV; 40 μ g/kg）与PTZ联合使用时，产生了α位移。光遗传学诱导的PD阈值（oPDT）基线随时间推移保持稳定，表明该指标适用于具有多种药理学操作的受试者内实验设计。
Network excitability is governed by synaptic efficacy, intrinsic excitability, and the circuitry in which these factors are expressed. The complex interplay between these factors determines how circuits function and, at the extreme, their susceptibility to seizure. We have developed a sensitive, quantitative estimate of network excitability in freely behaving mice using a novel optogenetic intensity-response procedure. Synchronous activation of deep sublayer CA1 pyramidal cells produces abnormal network-wide epileptiform population discharges (PDs) that are nearly indistinguishable from spontaneously-occurring interictal spikes (IISs). By systematically varying light intensity, and therefore the magnitude of the optogenetically-mediated current, we generated intensity-response curves using the probability of PD as the dependent variable. Manipulations known to increase excitability, such as sub-convulsive doses (20 mg/kg) of the chemoconvulsant pentylenetetrazol (PTZ), produced a leftward shift in the curve compared to baseline. The anti-epileptic drug levetiracetam (LEV; 40 mk/kg), in combination with PTZ, produced a rightward shift. Optogenetically-induced PD threshold (oPDT) baselines were stable over time, suggesting the metric is appropriate for within-subject experimental designs with multiple pharmacological manipulations.