Authors
Mashiel, A., Achvat, S., Schiller, Y.
Abstract
Objective: Ictogenesis results from transition of the cortical network between the asymptomatic interictal state to the symptomatic ictal state of seizures. Despite being the target of all anti-seizure therapies, its underlying mechanisms and dynamics remain incompletely understood Methods: We employed in vivo two-photon calcium imaging to simultaneously monitor excitatory CA1 pyramidal neurons (PNs) and either parvalbumin-(PV) or somatostatin-expressing (SST) inhibitory interneurons (INs) during seizure onset in acute 4-aminopyridine (4-AP) and chronic kainate models of temporal lobe epilepsy. Results: Acute seizures exhibited two distinct initiation patterns: an INs-first pattern, in which activation of interneurons preceded that of pyramidal neurons, and a simultaneous PNs-INs pattern, characterized by concurrent activation of both populations. Remarkably, individual mice often alternated between these two initiation modes across different seizures. In contrast, spontaneous seizures in the chronic KA model consistently displayed only the simultaneous PNs-INs initiation pattern. Optogenetic activation of PNs, PV-INs, or SST-INs, as well as chemogenetic inhibition of INs, each elicited pro-ictogenic effects, reinforcing the concept of dual initiation pathways in which seizures may be triggered by activation of either excitatory or inhibitory neuronal populations. At seizure onset in both models, inter-neuronal synchronization reliably exceeded that of pyramidal neurons. Moreover, the recruitment sequence of PNs, and to a lesser extent INs, was highly stereotyped across seizures, suggesting the existence of a conserved and robust seizure initiation circuit. Conclusions: Seizures can emerge via two distinct yet stable pathways, reflecting dynamic but stereotyped initiation patterns shaped by excitatory-inhibitory interactions within epileptic networks.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Nov 2025.
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