title: Optogenetic Low-Frequency Stimulation of Specific Neuronal Populations Abates Ictogenesis.
abstract: Despite many advances made in understanding the pathophysiology of epileptic disorders, seizures remain poorly controlled in approximately one-third of patients with mesial temporal lobe epilepsy. Here, we established the efficacy of cell type-specific low-frequency stimulation (LFS) in controlling ictogenesis in the mouse entorhinal cortex (EC) in anin vitrobrain slice preparation. Specifically, we used 1 Hz optogenetic stimulation of calcium/calmodulin-dependent protein kinase II-positive principal cells as well as of parvalbumin- or somatostatin-positive interneurons to study the effects of such repetitive activation on epileptiform discharges induced by 4-aminopyridine. We found that 1 Hz stimulation of any of these cell types reduced the frequency and duration of ictal discharges in some trials, while completely blocking them in others. The field responses evoked by the stimulation of each cell type revealed that their duration and amplitude were higher when principal cells were targeted. Furthermore, following a short period of silence ranging from 67 to 135 s, ictal discharges were re-established with similar duration and frequency as before stimulation; however, this period of silence was longer following principal cell stimulation compared with parvalbumin- or somatostatin-positive interneuron stimulation. Our results show that LFS of either excitatory or inhibitory cell networks in EC are effective in controlling ictogenesis. Although optogenetic stimulation of either cell type significantly reduced the occurrence of ictal discharges, principal cell stimulation resulted in a more prolonged suppression of ictogenesis, and, thus, it may constitute a better approach for controlling seizures.SIGNIFICANCE STATEMENTEpilepsy is a neurological disorder characterized by an imbalance between excitation and inhibition leading to seizures. Many epileptic patients do not achieve adequate seizure control using antiepileptic drugs. Low-frequency stimulation (LFS) is an alternative tool for controlling epileptiform activity in these patients. However, despite the temporal and spatial control offered by LFS, such a procedure lacks cell specificity, which may limit its efficacy. Using an optogenetic approach, we report here that LFS of two interneuron subtypes and, even more so, of principal cells can reliably shorten or abolish seizuresin vitroOur work suggests that targeted LFS may constitute a reliable means for controlling seizures in patients presenting with focal seizures.
authors.affiliation: Montreal Neurological Institute, and Departments of Neurology & Neurosurgery and Physiology, McGill University, Montréal, Québec H3A 2B4, Canada, and.
authors.forename: Zahra
authors.identifier: 0000-0001-8034-1566
authors.initials: Z
authors.lastname: Shiri
authors.affiliation: Montreal Neurological Institute, and Departments of Neurology & Neurosurgery and Physiology, McGill University, Montréal, Québec H3A 2B4, Canada, and.
authors.forename: Maxime
authors.identifier: 0000-0002-1593-7037
authors.initials: M
authors.lastname: Lévesque
authors.affiliation: Douglas Mental Health University Institute, McGill University, Montréal, Québec H4H 1R3, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Etter
authors.affiliation: Douglas Mental Health University Institute, McGill University, Montréal, Québec H4H 1R3, Canada.
authors.forename: Frédéric
authors.identifier: 0000-0003-3725-9561
authors.initials: F
authors.lastname: Manseau
authors.affiliation: Douglas Mental Health University Institute, McGill University, Montréal, Québec H4H 1R3, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Williams
authors.affiliation: Montreal Neurological Institute, and Departments of Neurology & Neurosurgery and Physiology, McGill University, Montréal, Québec H3A 2B4, Canada, and massimo.avoli@mcgill.ca.
authors.forename: Massimo
authors.initials: M
authors.lastname: Avoli
mesh_terms: D000818:Animals; D004599:Electric Stimulation Therapy / Q000379:methods*; D018728:Entorhinal Cortex / Q000503:physiopathology*; D004827:Epilepsy / Q000175:diagnosis / Q000503:physiopathology* / Q000517:prevention & control*; D005260:Female; D007395:Interneurons; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000503:physiopathology; D062308:Optogenetics / Q000379:methods*; D016896:Treatment Outcome
keywords: entorhinal cortex; ictogenesis; low-frequency stimulation; optogenetics