title: LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development.
abstract: The secreted leucine-rich glioma inactivated 1 (LGI1) protein is an important actor for human seizures of both genetic and autoimmune etiology: mutations in LGI1 cause inherited temporal lobe epilepsy, while LGI1 is involved in antibody-mediated encephalitis. Remarkably, Lgi1-deficient (Lgi1(-/-)) mice recapitulate the epileptic disorder and display early-onset spontaneous seizures. To understand how Lgi1-deficiency leads to seizures during postnatal development, we here investigated the early functional and structural defects occurring before seizure onset in Lgi1(-/-) mice. We found an increased excitatory synaptic transmission in hippocampal slices from Lgi1(-/-) mice. No structural alteration in the morphology of pyramidal cell dendrites and synapses was observed at this stage, indicating that Lgi1-deficiency is unlikely to trigger early developmental abnormalities. Consistent with the presynaptic subcellular localization of the protein, Lgi1-deficiency caused presynaptic defects, with no alteration in postsynaptic AMPA receptor activity in Lgi1-/- pyramidal cells before seizure onset. Presynaptic dysfunction led to increased synaptic glutamate levels, which were associated with hyperexcitable neuronal networks. Altogether, these data show that Lgi1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development. We therefore here reveal that increased presynaptic glutamate release is a key early event resulting from Lgi1-deficiency, which likely contributes to epileptogenesis.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013 Paris, France.|INSERM, U1127, ICM, Paris, F-75013 Paris, France.|CNRS, UMR 7225, ICM, Paris, F-75013 Paris, France.|ICM, Paris, F-75013 Paris, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Boillot
authors.affiliation: Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University, F-75005 Paris, France.
authors.forename: Chun-Yao
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013 Paris, France.|INSERM, U1127, ICM, Paris, F-75013 Paris, France.|CNRS, UMR 7225, ICM, Paris, F-75013 Paris, France.|ICM, Paris, F-75013 Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Allene
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013 Paris, France.|INSERM, U1127, ICM, Paris, F-75013 Paris, France.|CNRS, UMR 7225, ICM, Paris, F-75013 Paris, France.|ICM, Paris, F-75013 Paris, France.|Département de Génétique et de Cytogénétique, AP-HP Groupe hospitalier Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013 Paris, France.|INSERM, U1127, ICM, Paris, F-75013 Paris, France.|CNRS, UMR 7225, ICM, Paris, F-75013 Paris, France.|ICM, Paris, F-75013 Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
authors.affiliation: Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University, F-75005 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouach
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004827:Epilepsy / Q000503:physiopathology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D017966:Pyramidal Cells / Q000502:physiology; D009435:Synaptic Transmission
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C492120:Lgi1 protein, mouse; D011506:Proteins