Experimental Epilepsy Group, Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, 22184 Lund, Sweden, and Brain Repair and Imaging in Neural Systems (BRAINS) Unit, Department of Experimental Medical Sciences, Lund University Hospital, 22184 Lund, Sweden.
J Neurosci. 2014 Feb 26;34(9):3364-77. doi: 10.1523/JNEUROSCI.2734-13.2014.
Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy. In particular, the possibility to specifically activate by light-determined interneuron populations expressing channelrhodopsin-2 provides an unprecedented opportunity of exploring their contribution to physiological and pathological network activity. There are several subclasses of interneurons in cortical areas with different functional connectivity to the principal neurons (e.g., targeting their perisomatic or dendritic compartments). Therefore, one could optogenetically activate specific or a mixed population of interneurons and dissect their selective or concerted inhibitory action on principal cells. We chose to explore a conceptually novel strategy involving simultaneous activation of mixed populations of interneurons by optogenetics and study their impact on ongoing epileptiform activity in mouse acute hippocampal slices. Here we demonstrate that such approach results in a brief initial action potential discharge in CA3 pyramidal neurons, followed by prolonged suppression of ongoing epileptiform activity during light exposure. Such sequence of events was caused by massive light-induced release of GABA from ChR2-expressing interneurons. The inhibition of epileptiform activity was less pronounced if only parvalbumin- or somatostatin-expressing interneurons were activated by light. Our data suggest that global optogenetic activation of mixed interneuron populations is a more effective approach for development of novel therapeutic strategies for epilepsy, but the initial action potential generation in principal neurons needs to be taken in consideration.
光遗传学技术为双向控制神经元活动提供了强大的工具，并为研究兴奋性障碍（如癫痫）中发生的变化提供了可能。特别是，通过光确定表达通道视紫红质-2的中间神经元群体特异性激活的可能性，为探索它们对生理和病理网络活动的贡献提供了前所未有的机会。皮质区域中有几种中间神经元亚类，与主神经元具有不同的功能连接（例如，针对其胞体或树突隔室）。因此，可以光遗传学方式选择性或协同性地激活特定或混合的中间神经元群体，并剖析它们对主细胞的选择性或协同抑制作用。我们选择了探索一种涉及通过光遗传学同时激活混合的中间神经元群体的新概念性策略，并研究其对急性海马脑片中小鼠进行性癫痫样活动的影响。在这里，我们证明了这种方法会导致 CA3 锥体神经元的短暂初始动作电位放电，随后在光暴露期间持续抑制进行性癫痫样活动。这种事件序列是由表达 ChR2 的中间神经元大量光诱导释放 GABA 引起的。如果仅用光激活表达 Parvalbumin 或 Somatostatin 的中间神经元，则对癫痫样活动的抑制作用不那么明显。我们的数据表明，混合中间神经元群体的全局光遗传学激活是开发癫痫新治疗策略的更有效方法，但需要考虑主神经元中的初始动作电位产生。
