Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures
| Autor: | Jérôme Garrigue, Eric LeGuern, Morgane Boillot, Benoit Martin, Richard B. Miles, Vincent Navarro, Elise Marsan, Matthew P. Anderson, Béatrice Dufresnois, Katia Lehongre, Ekim Ozkaynak, Stéphanie Baulac, Saeko Ishida, Clément Huneau |
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| Přispěvatelé: | Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de neurosciences cognitives et d'imagerie cérébrale (LENA), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Biology Inhibitory postsynaptic potential 03 medical and health sciences Glutamatergic Epilepsy Mice 0302 clinical medicine Interneurons Seizures Conditional gene knockout medicine Animals GABAergic Neurons ComputingMilieux_MISCELLANEOUS 030304 developmental biology Mice Knockout Neurons 0303 health sciences Pyramidal Cells Limbic encephalitis Age Factors Intracellular Signaling Peptides and Proteins Brain Proteins Electroencephalography Original Articles medicine.disease Embryo Mammalian medicine.anatomical_structure nervous system Animals Newborn Convulsant biology.protein Neurology (clinical) Neuron Neuroscience 030217 neurology & neurosurgery Parvalbumin [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Brain-A Journal of Neurology Brain-A Journal of Neurology, Oxford University Press (OUP), 2014, 137 (11), pp.2984-2996. ⟨10.1093/brain/awu259⟩ Brain-A Journal of Neurology, 2014, 137 (11), pp.2984-2996. ⟨10.1093/brain/awu259⟩ |
| ISSN: | 0006-8950 1460-2156 |
| DOI: | 10.1093/brain/awu259⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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