GABAergic neurons can facilitate the propagation of cortical spreading depolarization: experiments in mouse neocortical slices and a novel neural field computational model

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 (K+) 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 K+ 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 K+ 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.Author summary: In this manuscript, we reveal mechanisms underlying the propagation of migraine related cortical spreading depression (CSD) by focusing on the role of GABAergic inhibitory neurons. To study the related mechanisms, we performed experiments in mouse brain slices and designed a new spatially extended neural field computational model. Our experiments show the facilitatory role that GABAergic neurons can have on CSD propagation. Our model generates accurate simulations of CSD in coherence with the experimental results. Moreover, it provides testable hypotheses on the mechanisms underlying CSD, in particular on the role of GABAergic neurons. The model is based on large populations of interconnected GABAergic and glutamatergic excitatory 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 and increase in their spiking activity can enhance CSD propagation. Finally, the simulations predict that the facilitating effect on CSD propagation is caused by a larger release of potasssium from GABAergic neurons at the CSD wave front when the populations are disinhibited.