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Brain. 2014 Nov;137(Pt 11):2984-96. doi: 10.1093/brain/awu259. Epub 2014 Sep 17.

Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures.

Author information

1
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.
2
5 Université de Rennes 1, LTSI, F-35000, Rennes, France 6 INSERM, U1099, F-35000, Rennes, France.
3
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.
4
8 Departments of Neurology and Pathology, Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, Massachusetts 02215, USA.
5
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.
6
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.

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.

KEYWORDS:

ADEAF; LGI1; conditional knockout; epilepsy; genetics

PMID:
25234641
PMCID:
PMC4208469
DOI:
10.1093/brain/awu259
[Indexed for MEDLINE]
Free PMC Article

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