Chemogenetic Recruitment of Specific Interneurons Suppresses Seizure Activity.
Chemogenetic Recruitment of Specific Interneurons Suppresses Seizure Activity.
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DOI：
10.3389/fncel.2018.00293
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发表时间：
2018
影响因子：
5.3
通讯作者：
Akerman CJ
中科院分区：
文献类型：
--
作者：
Cǎlin A;Stancu M;Zagrean AM;Jefferys JGR;Ilie AS;Akerman CJ
目前增强突触抑制的抗癫痫药物在减少几种类型的癫痫发作活动方面是有效的。然而，由于这些药物作用的广泛性，它们会产生明显的副作用，甚至产生矛盾的反应。最近发展的化学遗传学技术提供了以选择性和电路特异性的方式从药理学上招募内源性抑制机制的机会。在这里，我们使用化学遗传学来评估通过增强啮齿动物海马中三个主要中间神经元群体的突触输出来抑制癫痫样活动的潜力：小白蛋白（PV）、生长抑素（SST）和表达血管活性肠肽（VIP）的中间神经元。为了针对不同的神经元群体，将启动子特异性crer -重组酶小鼠与病毒介导的化学遗传构建物结合使用。然后在慢性耐药癫痫的体外模型中进行靶向电生理记录。此外，在急性触发癫痫发作活动的体内模型中进行了行为视频评分。脑切片的突触前和突触后全细胞记录显示，在化学发生激活后，三种中间神经元类型中的每一种都增加了它们的放电速率和突触输出。然而，中间神经元群对癫痫样放电表现出不同的影响。招募VIP中间神经元并没有改变癫痫样放电的总持续时间。相比之下，招募SST或PV中间神经元对癫痫样同步产生了强有力的抑制。PV中间神经元在每个细胞中表现出最强的效应，与其他细胞类型相比，其癫痫样活动的减少至少要大5倍。与此一致的是，我们发现PV中间神经元的体内化学发生募集抑制了80%以上的惊厥行为。我们的研究结果支持了选择性化学发生增强抑制性突触通路作为抗癫痫策略的可能性。
Current anti-epileptic medications that boost synaptic inhibition are effective in reducing several types of epileptic seizure activity. Nevertheless, these drugs can generate significant side-effects and even paradoxical responses due to the broad nature of their action. Recently developed chemogenetic techniques provide the opportunity to pharmacologically recruit endogenous inhibitory mechanisms in a selective and circuit-specific manner. Here, we use chemogenetics to assess the potential of suppressing epileptiform activity by enhancing the synaptic output from three major interneuron populations in the rodent hippocampus: parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) expressing interneurons. To target different neuronal populations, promoter-specific cre-recombinase mice were combined with viral-mediated delivery of chemogenetic constructs. Targeted electrophysiological recordings were then conducted in an in vitro model of chronic, drug-resistant epilepsy. In addition, behavioral video-scoring was performed in an in vivo model of acutely triggered seizure activity. Pre-synaptic and post-synaptic whole cell recordings in brain slices revealed that each of the three interneuron types increase their firing rate and synaptic output following chemogenetic activation. However, the interneuron populations exhibited different effects on epileptiform discharges. Recruiting VIP interneurons did not change the total duration of epileptiform discharges. In contrast, recruiting SST or PV interneurons produced robust suppression of epileptiform synchronization. PV interneurons exhibited the strongest effect per cell, eliciting at least a fivefold greater reduction in epileptiform activity than the other cell types. Consistent with this, we found that in vivo chemogenetic recruitment of PV interneurons suppressed convulsive behaviors by more than 80%. Our findings support the idea that selective chemogenetic enhancement of inhibitory synaptic pathways offers potential as an anti-seizure strategy.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
64.8
作者：
COBB, SR;BUHL, EH;SOMOGYI, P
通讯作者：
SOMOGYI, P
影响因子：
16.6
作者：
Kaetzel, Dennis;Nicholson, Elizabeth;Schorge, Stephanie;Walker, Matthew C.;Kullmann, Dimitri M.
通讯作者：
Kullmann, Dimitri M.
影响因子：
5.5
作者：
Cammarota, Mario;Losi, Gabriele;Carmignoto, Giorgio
通讯作者：
Carmignoto, Giorgio
影响因子：
4.6
作者：
Bergstrom, Rachel A.;Choi, Jee Hyun;Manduca, Armando;Shin, Hee-Sup;Worrell, Greg A.;Howe, Charles L.
通讯作者：
Howe, Charles L.