LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

Abstract

Autosomal dominant epilepsy with auditory features results from mutations in leucine-rich glioma-inactivated 1 (LGI1), a soluble glycoprotein secreted by neurons. Animal models of LGI1 depletion display spontaneous seizures, however, the function of LGI1 and the mechanisms by which deficiency leads to epilepsy are unknown. We investigated the effects of pure recombinant LGI1 and genetic depletion on intrinsic excitability, in the absence of synaptic input, in hippocampal CA3 neurons, a classical focus for epileptogenesis. Our data indicate that LGI1 is expressed at the axonal initial segment and regulates action potential firing by setting the density of the axonal Kv1.1 channels that underlie dendrotoxin-sensitive D-type potassium current.LGI1 deficiency incurs a >50% down-regulation of the expression of Kv1.1 and Kv1.2 via a posttranscriptional mechanism, resulting in a reduction in the capacity of axonal D-type current to limit glutamate release, thus contributing to epileptogenesis.LGI1 | Kv1 channels | D-type current | intrinsic excitability | epilepsy

Persistent sodium current blockers can suppress seizures caused by loss of low‐threshold D‐type potassium currents: Predictions from an in silico study of Kv1 channel disorders

“…While the effects of manipulations in D‐type currents have been studied intensively in many neuron types using the antagonist α‐dendrotoxin, K v 1‐related A‐type currents have been less extensively studied. Previous experiments have found that K v 1.1 and K v 1.4 channels may conduct A‐type currents when co‐assembling with auxiliary subunits K v β1 or K v β2 . Although our simulations suggest that changes in A‐type currents do not significantly affect neuronal excitability, further investigation is required to understand their role in neurons.…”

“…Associated epilepsy phenotypes can be refractory to existing antiepileptic medications, often with devastating sequelae. LGI1 encodes a protein that regulates the expression and function of K v 1 channels and AMPA receptors . In LGI1 knockout models, the expression of K v 1.1 and K v 1.2 channels is reduced by more than 50% .…”

“…LGI1 encodes a protein that regulates the expression and function of K v 1 channels and AMPA receptors . In LGI1 knockout models, the expression of K v 1.1 and K v 1.2 channels is reduced by more than 50% . Depletion of leucine‐rich glioma‐inactivated 1 protein also increases the release of glutamate and significantly reduces the expression of AMPA receptors .…”

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

“…Targeted deletion of Lgi1 in mice resulted in lethal myoclonic epileptic seizures . CA3 neurons of Lgi1 −/− hippocampal slice cultures exhibited an increased intrinsic neuronal excitability that may explain seizure generation …”

The clinical features, underlying immunology, and treatment of autoantibody‐mediated movement disorders

“…The highly consistent association between a distinctive clinical phenotype and the presence of LGI1 antibodies strongly suggests that they have a pathogenic role. This has been strengthened by in vitro data that implicate alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐receptors and potassium channels in the downstream mechanisms of LGI1‐modulation induced neuronal dysfunction . Other functional effects of the LGI1 autoantibodies include the downregulation of the LGI1 complex, which includes LGI1's natural binding partners a disintegrin and metalloproteinase domain‐containing protein 22 and 23 (ADAM22/23) .…”