LGI1 downregulation increases neuronal circuit excitability.
Kv1.1
LGI1
epilepsy
short-term plasticity
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
06
07
2020
revised:
29
09
2020
accepted:
29
09
2020
pubmed:
27
10
2020
medline:
4
3
2021
entrez:
26
10
2020
Statut:
ppublish
Résumé
Leucine-rich glioma-inactivated 1 (LGI1) is a secreted transsynaptic protein that interacts presynaptically with Kv1.1 potassium channels and a disintegrin and metalloprotease (ADAM) protein 23, and postsynaptically influences α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors through a direct link with the ADAM22 cell adhesion protein. Haploinsufficiency of LGI1 or autoantibodies directed against LGI1 are associated with human epilepsy, generating the hypothesis that a subacute reduction of LGI1 is sufficient to increase network excitability. We tested this hypothesis in ex vivo hippocampal slices and in neuronal cultures, by subacutely reducing LGI1 expression with shRNA. Injection of shRNA-LGI1 in the hippocampus increased dentate granule cell excitability and low-frequency facilitation of mossy fibers to CA3 pyramidal cell neurotransmission. Application of the Kv1 family blocker, α-dendrotoxin, occluded this effect, implicating the involvement of Kv1.1. This subacute reduction of LGI1 was also sufficient to increase neuronal network activity in neuronal primary culture. These results indicate that a subacute reduction in LGI1 potentiates neuronal excitability and short-term synaptic plasticity, and increases neuronal network excitability, opening new avenues for the treatment of limbic encephalitis and temporal lobe epilepsies.
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Lgi1 protein, mouse
0
RNA, Small Interfering
0
Kv1.1 Potassium Channel
147173-20-4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2836-2846Subventions
Organisme : H2020 Marie Skłodowska-Curie Actions
ID : 642881
Organisme : H2020 Marie Skłodowska-Curie Actions
ID : 658418
Organisme : Epilepsy Research UK
ID : F1701
Informations de copyright
© The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
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