Baspinar Emre, Simonti Martina, Srour Hadi, Desroches Mathieu, Avitabile Daniele, Mantegazza Massimo
MathNeuro Team, Inria Branch of the University of Montpellier, Montpellier, France.
Université de Montpellier, Montpellier, France.
PLoS Comput Biol. 2025 Jun 4;21(6):e1013099. doi: 10.1371/journal.pcbi.1013099. eCollection 2025 Jun.
Cortical spreading depolarization (CSD) is a wave of depolarization with local onset and extended propagation implicated in several pathological conditions. Its mechanisms have been extensively investigated, including our recent studies showing with experimental and computational approaches that the hyperactivity of GABAergic neurons' can initiate migraine-related CSD because of spiking-generated extracellular potassium ([Formula: see text]) build-up. However, less is known about the role played by GABAergic neurons in CSD propagation. Here we studied mechanisms of CSD propagation, focusing on the role of GABAergic neurons, with experiments performed in mouse brain slices and with a new spatially extended neural field computational model. Experimentally, we induced CSD by applying brief puffs of potassium chloride (KCl) in somatosensory cortex slices from wild type and VGAT-ChR2-tdtomato mice, which specifically express the excitatory opsin channelrhodopsin (ChR2) in GABAergic neurons. We evaluated the role of GABAergic neurons in CSD propagation by modulating their activity with optogenetic illumination and their synaptic connections with pharmacological tools. We have developed the computational model to obtain realistic simulations of both initiation and propagation of CSD. It includes large populations of interconnected excitatory and inhibitory neurons, as well as the effect of extracellular ion concentrations on their features. We found that the decrease of the synaptic activity of GABAergic neurons can enhance CSD propagation, because of the reduction of the inhibitory synaptic weight, whereas their spiking activity can enhance CSD propagation because of extracellular [Formula: see text] upload. However, differently than for CSD initiation, the latter effect is normally hidden by the action of GABAergic synaptic transmission. A reduction of GABAergic synaptic transmission, which can be observed in pathological states, can reveal the potentiating effect of the [Formula: see text] upload induced by GABAergic activation. The neural field model that we implemented can generate accurate simulations of CSD, providing testable hypotheses on mechanisms, and can also be used for modeling other (patho)-physiological activities of neuronal networks.
皮层扩散性去极化（CSD）是一种去极化波，起始于局部并扩展传播，与多种病理状况有关。其机制已得到广泛研究，包括我们最近的研究，通过实验和计算方法表明，GABA能神经元的过度活跃可因动作电位产生的细胞外钾离子（[公式：见正文]）积累而引发偏头痛相关的CSD。然而，关于GABA能神经元在CSD传播中所起的作用，人们了解较少。在这里，我们通过在小鼠脑片上进行实验以及使用一种新的空间扩展神经场计算模型，研究了CSD传播的机制，重点关注GABA能神经元的作用。在实验中，我们通过在野生型和VGAT-ChR2-tdTomato小鼠的体感皮层切片中短暂施加氯化钾（KCl）来诱导CSD，这些小鼠在GABA能神经元中特异性表达兴奋性视蛋白通道视紫红质（ChR2）。我们通过光遗传学照明调节其活性以及使用药理学工具调节其突触连接，来评估GABA能神经元在CSD传播中的作用。我们开发了计算模型，以获得CSD起始和传播的真实模拟。它包括大量相互连接的兴奋性和抑制性神经元，以及细胞外离子浓度对其特性的影响。我们发现，GABA能神经元突触活动的降低可增强CSD传播，这是由于抑制性突触权重的降低，而它们的动作电位活动可因细胞外[公式：见正文]上传而增强CSD传播。然而，与CSD起始不同的是，后一种效应通常被GABA能突触传递的作用所掩盖。在病理状态下可观察到的GABA能突触传递的减少，可揭示GABA能激活诱导的[公式：见正文]上传的增强作用。我们实现的神经场模型可以生成CSD的精确模拟，提供关于机制的可测试假设，并且还可用于模拟神经网络的其他（病理）生理活动。
