title: Parvalbumin-Positive Inhibitory Interneurons Oppose Propagation But Favor Generation of Focal Epileptiform Activity.
abstract: Parvalbumin (Pv)-positive inhibitory interneurons effectively control network excitability, and their optogenetic activation has been reported to block epileptic seizures. An intense activity in GABAergic interneurons, including Pv interneurons, before seizures has been described in different experimental models of epilepsy, raising the hypothesis that an increased GABAergic inhibitory signal may, under certain conditions, initiate seizures. It is therefore unclear whether the activity of Pv interneurons enhances or opposes epileptiform activities. Here we use a mouse cortical slice model of focal epilepsy in which the epileptogenic focus can be identified and the role of Pv interneurons in the generation and propagation of seizure-like ictal events is accurately analyzed by a combination of optogenetic, electrophysiological, and imaging techniques. We found that a selective activation of Pv interneurons at the focus failed to block ictal generation and induced postinhibitory rebound spiking in pyramidal neurons, enhancing neuronal synchrony and promoting ictal generation. In contrast, a selective activation of Pv interneurons distant from the focus blocked ictal propagation and shortened ictal duration at the focus. We revealed that the reduced ictal duration was a direct consequence of the ictal propagation block, probably by preventing newly generated afterdischarges to travel backwards to the original focus of ictal initiation. Similar results were obtained upon individual Pv interneuron activation by intracellular depolarizing current pulses. The functional dichotomy of Pv interneurons here described opens new perspectives to our understanding of how local inhibitory circuits govern generation and spread of focal epileptiform activities.
authors.affiliation: Neuroscience Institute, National Research Council and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Sessolo
authors.affiliation: Neuroscience Institute, National Research Council and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Marcon
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy, and.
authors.forename: Serena
authors.initials: S
authors.lastname: Bovetti
authors.affiliation: Neuroscience Institute, National Research Council and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Losi
authors.affiliation: Neuroscience Institute, National Research Council and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cammarota
authors.affiliation: NEST, Istituto Nanoscienze-National Research Council, 56127 Pisa, Italy.
authors.forename: Gian Michele
authors.initials: GM
authors.lastname: Ratto
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy, and giorgio.carmignoto@bio.unipd.it Tommaso.Fellin@iit.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fellin
authors.affiliation: Neuroscience Institute, National Research Council and Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy, giorgio.carmignoto@bio.unipd.it Tommaso.Fellin@iit.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Carmignoto
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology*; D002118:Calcium / Q000378:metabolism; D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism*; D010775:Photic Stimulation; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D014161:Transduction, Genetic; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists; D008164:Luminescent Proteins; D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D002118:Calcium
keywords: channelrhodopsin-2; cortex; epileptiform activity; optogenetics; parvalbumin; rebound spiking