Mutant LGI1 inhibits seizure-induced trafficking of Kv4.2 potassium channels

J Neurochem. 2012 Feb;120(4):611-21. doi: 10.1111/j.1471-4159.2011.07605.x.


Activity-dependent redistribution of ion channels mediates neuronal circuit plasticity and homeostasis, and could provide pro-epileptic or compensatory anti-epileptic responses to a seizure. Thalamocortical neurons transmit sensory information to the cerebral cortex and through reciprocal corticothalamic connections are intensely activated during a seizure. Therefore, we assessed whether a seizure alters ion channel surface expression and consequent neurophysiologic function of thalamocortical neurons. We report a seizure triggers a rapid (<2h) decrease of excitatory postsynaptic current (EPSC)-like current-induced phasic firing associated with increased transient A-type K(+) current. Seizures also rapidly redistributed the A-type K(+) channel subunit Kv4.2 to the neuronal surface implicating a molecular substrate for the increased K(+) current. Glutamate applied in vitro mimicked the effect, suggesting a direct effect of glutamatergic transmission. Importantly, leucine-rich glioma-inactivated-1 (LGI1), a secreted synaptic protein mutated to cause human partial epilepsy, regulated this seizure-induced circuit response. Human epilepsy-associated dominant-negative-truncated mutant LGI1 inhibited the seizure-induced suppression of phasic firing, increase of A-type K(+) current, and recruitment of Kv4.2 surface expression (in vivo and in vitro). The results identify a response of thalamocortical neurons to seizures involving Kv4.2 surface recruitment associated with dampened phasic firing. The results also identify impaired seizure-induced increases of A-type K(+) current as an additional defect produced by the autosomal dominant lateral temporal lobe epilepsy gene mutant that might contribute to the seizure disorder.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Excitatory Postsynaptic Potentials / genetics
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Neural Conduction / genetics
  • Neural Inhibition / genetics*
  • Neurons / metabolism
  • Neurons / pathology
  • Organ Culture Techniques
  • Protein Transport / genetics
  • Proteins / genetics*
  • Proteins / physiology
  • Seizures / metabolism*
  • Seizures / pathology
  • Seizures / prevention & control*
  • Shal Potassium Channels / antagonists & inhibitors*
  • Shal Potassium Channels / genetics
  • Shal Potassium Channels / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • Lgi1 protein, mouse
  • Proteins
  • Shal Potassium Channels