title: Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.
abstract: Leucin-rich, glioma inactivated 1 (LGI1) is a secreted protein linked to human seizures of both genetic and autoimmune aetiology. Mutations in the LGI1 gene are responsible for autosomal dominant temporal lobe epilepsy with auditory features, whereas LGI1 autoantibodies are involved in limbic encephalitis, an acquired epileptic disorder associated with cognitive impairment. We and others previously reported that Lgi1-deficient mice have early-onset spontaneous seizures leading to premature death at 2-3 weeks of age. Yet, where and when Lgi1 deficiency causes epilepsy remains unknown. To address these questions, we generated Lgi1 conditional knockout (cKO) mice using a set of universal Cre-driver mouse lines. Selective deletion of Lgi1 was achieved in glutamatergic pyramidal neurons during embryonic (Emx1-Lgi1cKO) or late postnatal (CaMKIIα-Lgi1cKO) developmental stages, or in gamma amino butyric acidergic (GABAergic) parvalbumin interneurons (PV-Lgi1cKO). Emx1-Lgi1cKO mice displayed early-onset and lethal seizures, whereas CaMKIIα-Lgi1cKO mice presented late-onset occasional seizures associated with variable reduced lifespan. In contrast, neither spontaneous seizures nor increased seizure susceptibility to convulsant were observed when Lgi1 was deleted in parvalbumin interneurons. Together, these data showed that LGI1 depletion restricted to pyramidal cells is sufficient to generate seizures, whereas seizure thresholds were unchanged after depletion in gamma amino butyric acidergic parvalbumin interneurons. We suggest that LGI1 secreted from excitatory neurons, but not parvalbumin inhibitory neurons, makes a major contribution to the pathogenesis of LGI1-related epilepsies. Our data further indicate that LGI1 is required from embryogenesis to adulthood to achieve proper circuit functioning.
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Boillot
authors.affiliation: 5 Université de Rennes 1, LTSI, F-35000, Rennes, France 6 INSERM, U1099, F-35000, Rennes, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Huneau
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Marsan
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Lehongre
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France 7 AP-HP, Hôpital de la Pitié-Salpêtrière, Epilepsy Unit, F-75013, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Navarro
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Saeko
authors.initials: S
authors.lastname: Ishida
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Dufresnois
authors.affiliation: 8 Departments of Neurology and Pathology, Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Ekim
authors.initials: E
authors.lastname: Ozkaynak
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Garrigue
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Miles
authors.affiliation: 5 Université de Rennes 1, LTSI, F-35000, Rennes, France 6 INSERM, U1099, F-35000, Rennes, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Martin
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France 9 AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, F-75013, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.affiliation: 8 Departments of Neurology and Pathology, Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Anderson
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, ICM, F-75013 Paris, France 4 Institut du Cerveau et de la Moelle épinière (ICM), F-75013, Paris, France stephanie.baulac@upmc.fr.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D004569:Electroencephalography; D004622:Embryo, Mammalian / Q000378:metabolism; D059330:GABAergic Neurons / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D017966:Pyramidal Cells / Q000378:metabolism; D012640:Seizures / Q000209:etiology* / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C492120:Lgi1 protein, mouse; D011506:Proteins
keywords: ADEAF; LGI1; conditional knockout; epilepsy; genetics