Reliable and Elastic Propagation of Cortical Seizures In Vivo

Abstract

Mapping the fine-scale neural activity that underlies epilepsy is key to identify potential control targets of this frequently intractable disease. Yet, the detailed in vivo dynamics of seizure progression in cortical microcircuits remain poorly understood. We combine fast two-photon calcium imaging (30-Hz) with LFP recordings to map, cell by cell, the spread of locally induced (4-AP or picrotoxin) seizures in anesthetized and awake mice. Using single-layer and microprism-assisted multi-layer imaging in different cortical areas we uncover reliable recruitment of local neural populations within and across cortical layers, and find layer-specific temporal delays, suggesting an initial supra-granular invasion followed by deep-layer recruitment during lateral seizure spread. Intriguingly, despite consistent progression pathways, successive seizures show pronounced temporal variability that critically depends on GABAergic inhibition. We propose an epilepsy circuit model resembling an elastic meshwork wherein ictal progression faithfully follows preexistent pathways but varies flexibly in time, depending on the local inhibitory restraint.

Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language‐related NMDA receptor subunit gene Grin2a

“…Consistently, power spectrum and current source density analyses indicated the possible involvement of the granular neocortical layer that receives afferent connections from the thalamus. In addition, our data indicated the participation of supragranular and infragranular layers, hence suggesting an alternative and nonexclusive intracortical mechanism where epileptiform activity would propagate through horizontal pathways, as proposed previously . Whatever their mechanism(s), discharges were rarely detected—and not in all KO pups.…”

Layer‐ and Cell‐Specific Recruitment Dynamics during Epileptic Seizures In Vivo

“…Whereas at the site of seizure onset recruitment of supra‐ and infragranular layers showed diverse recruitment dynamics patterns, with rapid synchronous recruitment of layer 2/3 and 4 neurons versus sluggish asynchronous recruitment of layer 5 PNs, propagated seizures showed uniform recruitment dynamics in all layers, consisting of a gradually spreading pattern, with layer 2/3 preceding layer 5 recruitment. Importantly, in contrast to our study, Wenzel at al did not record from INs, and thus the relative recruitment dynamics of PNs and INs during seizure propagation was not studied.…”

“…Consistent with our findings, a previous study that also used in vivo 2‐photon calcium imaging of GCaMP6‐expressing neurons to study propagation of in vivo 4AP‐ and PTX‐induced neocortical seizures reported neocortical seizures that initially propagated in the supragranular layers and only later involved the infragranular layer. They further found that PV‐expressing INs controlled the propagation pattern of these seizures . In contrast to this study, we concentrated on seizure initiation, specifically at the site of seizure onset, or at least in close proximity to it.…”

“…Consistent with this possibility is that we did not see temporal differences between different regions of our imaging field, which extended over several hundreds of microns. Comparison of our findings with those of Wenzel et al indicated significant differences in the recruitment dynamics of excitatory neurons during seizure initiation and propagation. Whereas at the site of seizure onset recruitment of supra‐ and infragranular layers showed diverse recruitment dynamics patterns, with rapid synchronous recruitment of layer 2/3 and 4 neurons versus sluggish asynchronous recruitment of layer 5 PNs, propagated seizures showed uniform recruitment dynamics in all layers, consisting of a gradually spreading pattern, with layer 2/3 preceding layer 5 recruitment.…”

“…Focal seizures are generated at the epileptogenic zone and typically propagate from the site of onset to adjacent and more distant cortical regions. Previous studies have examined the recruitment dynamics of excitatory PNs and inhibitory INs during propagation of neocortical seizures in vitro and in vivo . However, little is known about the dynamics underlying seizure initiation at the site of seizure onset.…”