发作前期抑制性中间神经元功能障碍反常导致其反弹过度兴奋,并引发德拉维特综合征的低电压快发作癫痫。
Preictal dysfunctions of inhibitory interneurons paradoxically lead to their rebound hyperactivity and to low-voltage-fast onset seizures in Dravet syndrome.
机构信息
University Cote d'Azur, Institute of Molecular and Cellular Pharmacology, Valbonne-Sophia Antipolis 06560, France.
CNRS UMR 7275, Valbonne-Sophia Antipolis 06560, France.
出版信息
Proc Natl Acad Sci U S A. 2024 Jun 4;121(23):e2316364121. doi: 10.1073/pnas.2316364121. Epub 2024 May 29.
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 pathogenic variant, as well as epidural electrocorticograms, hippocampal local field potentials, and hippocampal single-unit neuronal activities in and 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 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.
癫痫有许多特定的机制。了解导致癫痫发作的神经动力学对于揭示病理机制和开发治疗方法很重要。我们研究了癫痫患者和 Dravet 综合征(DS)小鼠模型中导致惊厥性癫痫发作的电生理活动和神经动力学,DS 是一种发育性和癫痫性脑病,其中 GABA 能神经元的低兴奋性被认为是主要的功能障碍。我们分析了携带致病性变异的 DS 患者的脑电图、硬膜外皮层电图、海马局部场电位和 和 DS 小鼠的海马单细胞神经元活动。引人注目的是,大多数癫痫发作在患者和小鼠中都具有低电压快速起始的特征,这被认为是由 GABA 能中间神经元的过度兴奋引起的,与 DS 的主要病理机制相反。分析单细胞记录,我们观察到在癫痫发作前(发作前)期间,假定中间神经元的放电时间组织紊乱先于其在发作开始时活动的增加,以及整个神经元网络。此外,我们在 和 小鼠的海马和皮质场电位以及患者 EEG 的频谱特征中发现了发作前早期特征,这与我们在单个神经元中观察到的功能障碍一致,并允许进行癫痫发作预测。因此,中间神经元的紊乱发作前活动导致它们在全身性癫痫发作开始时过度兴奋,其具有低电压快速特征,类似于其他癫痫发作中观察到的特征,并且由 GABA 能神经元的过度兴奋引发。发作前的频谱特征可用作预测性癫痫发作生物标志物。