Centre for Discovery Brain Sciences, Simons Initiative for the Developing Brain, Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
Simons Initiative for the Developing Brain and Patrick Wild Centre, University of Edinburgh, Edinburgh, UK.
Brain. 2021 Jun 22;144(5):1576-1589. doi: 10.1093/brain/awab042.
Seizures can emerge from multiple or large foci in temporal lobe epilepsy, complicating focally targeted strategies such as surgical resection or the modulation of the activity of specific hippocampal neuronal populations through genetic or optogenetic techniques. Here, we evaluate a strategy in which optogenetic activation of medial septal GABAergic neurons, which provide extensive projections throughout the hippocampus, is used to control seizures. We utilized the chronic intrahippocampal kainate mouse model of temporal lobe epilepsy, which results in spontaneous seizures and as is often the case in human patients, presents with hippocampal sclerosis. Medial septal GABAergic neuron populations were immunohistochemically labelled and were not reduced in epileptic conditions. Genetic labelling with mRuby of medial septal GABAergic neuron synaptic puncta and imaging across the rostral to caudal extent of the hippocampus, also indicated an unchanged number of putative synapses in epilepsy. Furthermore, optogenetic stimulation of medial septal GABAergic neurons consistently modulated oscillations across multiple hippocampal locations in control and epileptic conditions. Finally, wireless optogenetic stimulation of medial septal GABAergic neurons, upon electrographic detection of spontaneous hippocampal seizures, resulted in reduced seizure durations. We propose medial septal GABAergic neurons as a novel target for optogenetic control of seizures in temporal lobe epilepsy.
癫痫发作可能起源于颞叶癫痫的多个或大病灶，从而使手术切除或通过遗传或光遗传学技术调节特定海马神经元群体的活动等针对病灶的策略变得复杂。在这里，我们评估了一种策略，即通过光遗传学激活内侧隔核 GABA 能神经元来控制癫痫发作，内侧隔核 GABA 能神经元广泛投射到整个海马体。我们利用慢性海马内海人酸颞叶癫痫小鼠模型，该模型会导致自发性癫痫发作，并且与人类患者的情况一样，通常伴有海马硬化。内侧隔核 GABA 能神经元群体通过免疫组织化学标记进行标记，在癫痫状态下并未减少。内侧隔核 GABA 能神经元突触小体的 mRuby 基因标记以及对海马体头侧到尾侧范围的成像，也表明癫痫发作时潜在突触数量没有变化。此外，内侧隔核 GABA 能神经元的光遗传学刺激在对照和癫痫状态下一致地调节了多个海马体部位的振荡。最后，在电生理检测到自发性海马体癫痫发作时，无线光遗传学刺激内侧隔核 GABA 能神经元可减少癫痫发作持续时间。我们提出内侧隔核 GABA 能神经元是颞叶癫痫发作的光遗传学控制的一个新靶点。
