Feedforward inhibition ahead of ictal wavefronts is provided by both parvalbumin‐ and somatostatin‐expressing interneurons

Abstract

Key points There is a rapid interneuronal response to focal activity in cortex, which restrains laterally propagating activity, including spreading epileptiform activity. The interneuronal response involves intense activation of both parvalbumin‐ and somatostatin‐expressing interneurons. Interneuronal bursting is time‐locked to glutamatergic barrages in the pre‐ictal period. Ca 2+ imaging using conditional expression of GCaMP6f provides an accurate readout of the evolving firing patterns in both types of interneuron. The activation profiles of the two interneuronal classes are temporally offset, with the parvalbumin population being activated first, and typically, at higher rates. Abstract Previous work has described powerful restraints on laterally spreading activity in cortical networks, arising from a rapid feedforward interneuronal response to focal activity. This response is particularly prominent ahead of an ictal wavefront. Parvalbumin‐positive interneurons are considered to be critically involved in this feedforward inhibition, but it is not known what role, if any, is provided by somatostatin‐expressing interneurons, which target the distal dendrites of pyramidal cells. We used a combination of electrophysiology and cell class‐specific Ca 2+ imaging in mouse brain slices bathed in 0 Mg 2+ medium to characterize the activity profiles of pyramidal cells and parvalbumin‐ and somatostatin‐expressing interneurons during epileptiform activation. The GCaMP6f signal strongly correlates with the level of activity for both interneuronal classes. Both interneuronal classes participate in the feedfoward inhibition. This contrasts starkly with the pattern of pyramidal recruitment, which is greatly delayed. During these barrages, both sets of interneurons show intense bursting, at rates up to 300Hz, which is time‐locked to the glutamatergic barrages. The activity of parvalbumin‐expressing interneurons appears to peak early in the pre‐ictal period, and can display depolarizing block during the ictal event. In contrast, somatostatin‐expressing interneuronal activity peaks significantly later, and firing persists throughout the ictal events. Interictal events appear to be very similar to the pre‐ictal period, albeit with slightly lower firing rates. Thus, the inhibitory restraint arises from a coordinated pattern of activity in the two main classes of cortical interneurons.

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

“…Consistent with our findings regarding cell‐specific recruitment dynamics of excitatory PNs, and PV‐ and SOM‐expressing INs during seizures are the results of 2 recently published papers . They also reported different recruitment dynamics of PNs compared to PV‐ and SOM‐expressing INs during the preictal and ictal phases during propagation of magnesium free induced seizures in brain slices in vitro, and the preictal and ictal phases of pilocarpine‐ and pentylenetetrazol‐induced hippocampal seizures in vivo .…”

“…Importantly, in contrast to our study, Wenzel at al 23 2 recently published papers. 22,31 They also reported different recruitment dynamics of PNs compared to PV-and SOM-expressing INs during the preictal and ictal phases during propagation of magnesium free induced seizures in brain slices in vitro, and the preictal and ictal phases of pilocarpine-and pentylenetetrazol-induced hippocampal seizures in vivo. 31 Importantly, these studies concentrated on the dynamics over longer time windows (seconds), whereas we concentrated on much shorter time windows (<1 second) at the onset of spikes and seizures.…”

Divergent paths to seizure‐like events

“…In contrast, the 0 Mg 2+ model can only be used in vitro (it is harder to remove ions than it is to add a drug), but it, too, involves intense bursts of interneuronal activity (Trevelyan et al, ; Trevelyan et al, ; Parrish et al, ), and evidence of short‐term changes in GABAergic function (Ellender et al, ; Raimondo et al, ), although, unlike the 4AP model, the interneuronal activity initially appears to act as a restraint on the spreading epileptiform discharges (Trevelyan and Schevon, ; Trevelyan, ). It is important to resolve these two contrasting views of the role of the interneuronal bursting.…”

Propagating activity in neocortex, mediated by gap-junctions and modulated by extracellular potassium

“…The primary effect of enhancing the electrical coupling of interneurons, in this way, will be to extend the inhibitory surround during focal cortical activation (Prince & Wilder, 1967; Schwartz & Bonhoeffer, 2001; Trevelyan et al ., 2006; Parrish et al ., 2019), while also enhancing coordination of this inhibitory effect. Interneuronal activity at this time, however, is a double edged sword, because there is now good evidence that these neurons may become active drivers of epileptic discharges, if pyramidal cells become loaded with chloride (Huberfeld et al ., 2007; Dzhala et al ., 2010; Avoli & de Curtis, 2011; Ellender et al ., 2014; Pallud et al ., 2014; Alfonsa et al ., 2015; Raimondo et al ., 2015; Alfonsa et al ., 2016; Chang et al ., 2018; Magloire et al ., 2019).…”