Dynamic, Cell-Type-Specific Roles for GABAergic Interneurons in a Mouse Model of Optogenetically Inducible Seizures

Abstract

SUMMARY GABAergic interneurons play critical roles in seizures, but it remains unknown whether these vary across interneuron subtypes or evolve during a seizure. This uncertainty stems from the unpredictable timing of seizures in most models, which limits neuronal imaging or manipulations around the seizure onset. Here, we describe a mouse model for optogenetic seizure induction. Combining this with calcium imaging, we find that seizure onset rapidly recruits parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptitde (VIP)-expressing interneurons, whereas excitatory neurons are recruited several seconds later. Optogenetically inhibiting VIP interneurons consistently increased seizure threshold and reduced seizure duration. Inhibiting PV+ and SOM+ interneurons had mixed effects on seizure initiation, but consistently reduced seizure duration. Thus, while their roles may evolve during seizures, PV+ and SOM+ interneurons ultimately help maintain ongoing seizures. These results show how an optogenetically-induced seizure model can be leveraged to pinpoint a new target for seizure control: VIP interneurons.

Reliable and Elastic Propagation of Cortical Seizures In Vivo

“…There is evidence, including the data presented here, that the local interaction of excitatory and inhibitory circuits is crucial for successful or failed ictal progression (Cammarota et al, 2013; Hunt et al, 2013; Khoshkhoo et al, 2017; Sessolo et al, 2015; Trevelyan et al, 2006; Ziburkus et al, 2006). While several recent studies have shown promising results with respect to cell sub-population based therapeutic seizure intervention (Krook-Magnuson et al, 2013; Ledri et al, 2014), others have raised concerns about the potential seizure promoting effects of such therapies (Avoli and de Curtis, 2011; Fujiwara-Tsukamoto et al, 2010; Gnatkovsky et al, 2008; Grasse et al, 2013; Sessolo et al, 2015).…”

“…Interestingly, and consistently in awake mice, interictal periods and seizure durations displayed a rather irregular pattern. At times, ictal activity failed to invade or only incompletely penetrated the imaged territory (Figure 5B left, Figure 5C left), and there was a consistent delay between the electrographic seizure onset and optical break-in, on the scale of seconds (Figure 5B and C, magnified portions) (Khoshkhoo et al, 2017; Martinet et al, 2015). This observation could be explained by a much slower temporal seizure progression imaged during wakefulness as compared to the anesthetized condition (4-AP: 0.0215 ± 0.003 mm/sec [5exp., awake] versus 0.64 ± 0.18 mm/sec [7exp., anesthetized]).…”

“…However, individual calcium deflections could only be directly related to lower frequency ictal activity towards the end of seizures (see e.g. movie S2), because even fast calcium indicators like OGB-1 or GCaMP6f have too low temporal kinetics to resolve individual LFP deflections during tonic ictal firing (Khoshkhoo et al, 2017). The propagation velocity of the optical invasion of the field of view was similar to the Jacksonian march described in humans and experimental seizure models where inhibition is intact (7 experiments [exp.]…”

Low‐voltage fast seizures in humans begin with increased interneuron firing

“…Calcium imaging of optogenetically kindled neocortical seizures demonstrates that inhibitory parvalbumin and somatostatin interneurons are activated prior to the excitatory neurons in the SOZ. 43 The mechanism by which the specific excitatory/inhibitory imbalance at LVF onset promotes seizure genesis is not yet resolved but may involve depolarizing GABAergic activity 45 or potassium and chloride efflux due to activation of the KCC2 cotransporter. 46,47 It is possible that novel pharmacological interventions could reduce inhibitory interneuron overactivation and thereby prevent seizure evolution.…”

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

“…[5][6][7][8] These effects have been obtained by inhibiting excitatory principal cells 6 or by increasing the excitability of inhibitory interneurons. 9 However, it has been reported that optogenetic stimulation of interneurons can also trigger ictal discharges in vitro, in the 4-aminopyridine (4AP) model. 9 However, it has been reported that optogenetic stimulation of interneurons can also trigger ictal discharges in vitro, in the 4-aminopyridine (4AP) model.…”