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

Journal of neurochemistry | Feb 16, 2012

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.

Pubmed ID: 22122031 RIS Download

Mesh terms: Animals | Cerebral Cortex | Excitatory Postsynaptic Potentials | Male | Mice | Mice, Transgenic | Mutation | Neural Conduction | Neural Inhibition | Neurons | Organ Culture Techniques | Protein Transport | Proteins | Seizures | Shal Potassium Channels

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Associated grants

  • Agency: NINDS NIH HHS, Id: R03 NS052521
  • Agency: NINDS NIH HHS, Id: R21 NS070295
  • Agency: NINDS NIH HHS, Id: R01 NS057444
  • Agency: NIMH NIH HHS, Id: F32 MH087085
  • Agency: NINDS NIH HHS, Id: R01 NS081916
  • Agency: NINDS NIH HHS, Id: R21NS070295
  • Agency: NINDS NIH HHS, Id: K02 NS054674-05
  • Agency: NINDS NIH HHS, Id: K02 NS054674
  • Agency: NINDS NIH HHS, Id: R03 NS052521-02
  • Agency: NINDS NIH HHS, Id: R01 NS057444-04

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