Premium
LGI1 downregulation increases neuronal circuit excitability
Author(s) -
Lugarà Eleonora,
Kaushik Rahul,
Leite Marco,
Chabrol Elodie,
Dityatev Alexander,
Lignani Gabriele,
Walker Matthew C.
Publication year - 2020
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16736
Subject(s) - neuroscience , hippocampal formation , neurotransmission , biology , premovement neuronal activity , microbiology and biotechnology , receptor , biochemistry
Objective 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. Methods We tested this hypothesis in ex vivo hippocampal slices and in neuronal cultures, by subacutely reducing LGI1 expression with shRNA. Results 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. Significance 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.