title: Mutant LGI1 inhibits seizure-induced trafficking of Kv4.2 potassium channels.
abstract: 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.
authors: Departments of Neurology and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Stephen E P
authors: SE
authors: Smith
authors: Lin
authors: L
authors: Xu
authors: Michael R
authors: MR
authors: Kasten
authors: Matthew P
authors: MP
authors: Anderson
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009431:Neural Conduction / Q000235:genetics; D009433:Neural Inhibition / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D012640:Seizures / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C492120:Lgi1 protein, mouse; D011506:Proteins; D051672:Shal Potassium Channels