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

• Published in: Annals of neurology Vol. 87; no. 1; pp. 97 - 115
• Main Authors: Aeed, Fadi, Shnitzer, Tal, Talmon, Ronen, Schiller, Yitzhak
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-01-2020; Wiley Subscription Services, Inc
• Subjects: 4-Aminopyridine; Action Potentials - physiology; Activation; Algorithms; Animals; Calcium; Calcium imaging; Cerebral cortex; Convulsions & seizures; Dynamics; Epilepsy; Female; In vivo methods and tests; Interneurons; Interneurons - metabolism; Interneurons - physiology; Learning algorithms; Machine Learning; Male; Mice; Neocortex; Neurons; Parvalbumin; Pyramidal cells; Pyramidal Cells - physiology; Recruitment; Recruitment, Neurophysiological - physiology; Seizures; Seizures - chemically induced; Seizures - physiopathology; Somatostatin; Somatostatin - metabolism; Spikes; Subpopulations
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25628

Objective
To investigate the network dynamics mechanisms underlying differential initiation of epileptic interictal spikes and seizures.
Methods
We performed combined in vivo 2‐photon calcium imaging from different targeted neuronal subpopulations and extracellular electrophysiological recordings during 4‐aminopyridine–induced neocortical spikes and seizures.
Results
Both spikes and seizures were associated with intense synchronized activation of excitatory layer 2/3 pyramidal neurons (PNs) and to a lesser degree layer 4 neurons, as well as inhibitory parvalbumin‐expressing interneurons (INs). In sharp contrast, layer 5 PNs and somatostatin‐expressing INs were gradually and asynchronously recruited into the ictal activity during the course of seizures. Within layer 2/3, the main difference between onset of spikes and seizures lay in the relative recruitment dynamics of excitatory PNs compared to parvalbumin‐ and somatostatin‐expressing inhibitory INs. Whereas spikes exhibited balanced recruitment of PNs and parvalbumin‐expressing INs, during seizures IN responses were reduced and less synchronized than in layer 2/3 PNs. Similar imbalance was not observed in layers 4 or 5 of the neocortex. Machine learning–based algorithms we developed were able to distinguish spikes from seizures based solely on activation dynamics of layer 2/3 PNs at discharge onset.
Interpretation
During onset of seizures, the recruitment dynamics markedly differed between neuronal subpopulations, with rapid synchronous recruitment of layer 2/3 PNs, layer 4 neurons, and parvalbumin‐expressing INs and gradual asynchronous recruitment of layer 5 PNs and somatostatin‐expressing INs. Seizures initiated in layer 2/3 due to a dynamic mismatch between local PNs and inhibitory INs, and only later spread to layer 5 by gradually and asynchronously recruiting PNs in this layer. ANN NEUROL 2020;87:97–115