PDF(Pubmed)
Abstract：
Epilepsies have numerous specific mechanisms. The understanding of neural dynamics leading to seizures is important for disclosing pathological mechanisms and developing therapeutic approaches. We investigated electrographic activities and neural dynamics leading to convulsive seizures in patients and mouse models of Dravet syndrome (DS), a developmental and epileptic encephalopathy in which hypoexcitability of GABAergic neurons is considered to be the main dysfunction. We analyzed EEGs from DS patients carrying a SCN1A pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials, and hippocampal single-unit neuronal activities in Scn1a+/- and Scn1aRH/+ DS mice. Strikingly, most seizures had low-voltage-fast onset in both patients and mice, which is thought to be generated by hyperactivity of GABAergic interneurons, the opposite of the main pathological mechanism of DS. Analyzing single-unit recordings, we observed that temporal disorganization of the firing of putative interneurons in the period immediately before the seizure (preictal) precedes the increase of their activity at seizure onset, together with the entire neuronal network. Moreover, we found early signatures of the preictal period in the spectral features of hippocampal and cortical field potential of Scn1a mice and of patients\' EEG, which are consistent with the dysfunctions that we observed in single neurons and that allowed seizure prediction. Therefore, the perturbed preictal activity of interneurons leads to their hyperactivity at the onset of generalized seizures, which have low-voltage-fast features that are similar to those observed in other epilepsies and are triggered by hyperactivity of GABAergic neurons. Preictal spectral features may be used as predictive seizure biomarkers.
摘要：
癫痫有许多特定的机制。对导致癫痫发作的神经动力学的理解对于揭示病理机制和开发治疗方法很重要。我们研究了导致Dravet综合征（DS）患者和小鼠模型惊厥性癫痫发作的电图活动和神经动力学，发育性和癫痫性脑病，其中GABA能神经元的兴奋性低下被认为是主要功能障碍。我们分析了携带SCN1A致病变异的DS患者的脑电图，以及硬膜外脑电图,海马局部场电位,Scn1a+/-和Scn1aRH/+DS小鼠海马单单位神经元活动。引人注目的是，大多数癫痫发作在患者和小鼠中都是低电压快速发作的，这被认为是由GABA能中间神经元的过度活跃产生的，与DS的主要病理机制相反。分析单单元记录，我们观察到，在癫痫发作（发作前）之前，假定的中间神经元放电的时间混乱先于癫痫发作时的活动增加，以及整个神经元网络。此外，我们在Scn1a小鼠和患者脑电图的海马和皮质场电位的频谱特征中发现了发作前期的早期特征，这与我们在单个神经元中观察到的功能障碍一致，并允许癫痫发作预测。因此,中间神经元的扰动的发作前活动导致它们在全身性癫痫发作时的过度活跃，具有与其他癫痫中观察到的类似的低电压快速特征，并且由GABA能神经元的过度活跃触发。发作前光谱特征可用作预测性癫痫发作生物标志物。
