title: Optogenetic activation of VGLUT2-expressing excitatory neurons blocks epileptic seizure-like activity in the mouse entorhinal cortex.
abstract: We investigated whether an anti-epileptic effect is obtained by selectively activating excitatory neurons expressing ChR2 under the promoter for the synaptic vesicular glutamate transporter 2 (VGLUT2). VGLUT2-expressing cells were optically stimulated while local field potential and whole-cell patch-clamp recordings were performed in mouse entorhinal cortical slices perfused with the proconvulsive compound 4-aminopyridine (4-AP). In control conditions, blue light flashes directly depolarized the majority of putative glutamatergic cells, which in turn synaptically excited GABAergic interneurons. During bath perfusion with 4-AP, photostimuli triggered a fast EPSP-IPSP sequence which was often followed by tonic-clonic seizure-like activity closely resembling spontaneous ictal discharges. The GABAA-receptor antagonist gabazine blocked the progression of both light-induced and spontaneous seizures. Surprisingly, prolonged photostimuli delivered during ongoing seizures caused a robust interruption of synchronous discharges. Such break was correlated with a membrane potential depolarization block in principal cells, while putative GABAergic interneurons changed their firing activity from a burst-like to an irregular single-spike pattern. These data suggest that photostimulation of glutamatergic neurons triggers seizure-like activity only in the presence of an intact GABAergic transmission and that selectively activating the same glutamatergic cells robustly interrupts ongoing seizures by inducing a strong depolarization block, resulting in the disruption of paroxysmal burst-like firing.
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy.|Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Latefa
authors.initials: L
authors.lastname: Yekhlef
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Breschi
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Taverna
mesh_terms: D000200:Action Potentials; D000818:Animals; D018728:Entorhinal Cortex / Q000473:pathology*; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000502:physiology*; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D012640:Seizures / Q000503:physiopathology*; D050599:Vesicular Glutamate Transport Protein 2
chemical_list: C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2