title: Reducing premature KCC2 expression rescues seizure susceptibility and spine morphology in atypical febrile seizures.
abstract: Atypical febrile seizures are considered a risk factor for epilepsy onset and cognitive impairments later in life. Patients with temporal lobe epilepsy and a history of atypical febrile seizures often carry a cortical malformation. This association has led to the hypothesis that the presence of a cortical dysplasia exacerbates febrile seizures in infancy, in turn increasing the risk for neurological sequelae. The mechanisms linking these events are currently poorly understood. Potassium-chloride cotransporter KCC2 affects several aspects of neuronal circuit development and function, by modulating GABAergic transmission and excitatory synapse formation. Recent data suggest that KCC2 downregulation contributes to seizure generation in the epileptic adult brain, but its role in the developing brain is still controversial. In a rodent model of atypical febrile seizures, combining a cortical dysplasia and hyperthermia-induced seizures (LHS rats), we found a premature and sustained increase in KCC2 protein levels, accompanied by a negative shift of the reversal potential of GABA. In parallel, we observed a significant reduction in dendritic spine size and mEPSC amplitude in CA1 pyramidal neurons, accompanied by spatial memory deficits. To investigate whether KCC2 premature overexpression plays a role in seizure susceptibility and synaptic alterations, we reduced KCC2 expression selectively in hippocampal pyramidal neurons by in utero electroporation of shRNA. Remarkably, KCC2 shRNA-electroporated LHS rats show reduced hyperthermia-induced seizure susceptibility, while dendritic spine size deficits were rescued. Our findings demonstrate that KCC2 overexpression in a compromised developing brain increases febrile seizure susceptibility and contribute to dendritic spine alterations.
authors.affiliation: Neurosciences Department, Université de Montréal, 2960 Chemin de la Tour, Montréal, Québec H3T 1N8, Canada; CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Awad
authors.affiliation: CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Nathalie T
authors.initials: NT
authors.lastname: Sanon
authors.affiliation: CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Chattopadhyaya
authors.affiliation: CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Josianne Nunes
authors.initials: JN
authors.lastname: Carriço
authors.affiliation: CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ouardouz
authors.affiliation: Neurosciences Department, Université de Montréal, 2960 Chemin de la Tour, Montréal, Québec H3T 1N8, Canada; CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gagné
authors.affiliation: CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duss
authors.affiliation: Neurosciences Department, Université de Montréal, 2960 Chemin de la Tour, Montréal, Québec H3T 1N8, Canada; CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Wolf
authors.affiliation: CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Desgent
authors.affiliation: Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cancedda
authors.affiliation: Neurosciences Department, Université de Montréal, 2960 Chemin de la Tour, Montréal, Québec H3T 1N8, Canada; CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada. Electronic address: lionel.carmant@umontreal.ca.
authors.forename: Lionel
authors.initials: L
authors.lastname: Carmant
authors.affiliation: Neurosciences Department, Université de Montréal, 2960 Chemin de la Tour, Montréal, Québec H3T 1N8, Canada; CHU Sainte-Justine Research Center, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec H3T 1C5, Canada. Electronic address: graziella.dicristo@recherche-ste-justine.qc.ca.
authors.forename: Graziella
authors.initials: G
authors.lastname: Di Cristo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology*; D004198:Disease Susceptibility / Q000378:metabolism; D004827:Epilepsy / Q000503:physiopathology; D008569:Memory Disorders / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D017966:Pyramidal Cells / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D003294:Seizures, Febrile / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D027981:Symporters / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D027981:Symporters; D000096922:K Cl- Cotransporters
keywords: Atypical febrile seizures; Cortical dysplasia; Dendritic spines; Hippocampus; In utero electroporation; KCC2; Seizure susceptibility; Temporal lobe epilepsy; shRNA