期刊
JOURNAL OF NEUROCHEMISTRY
卷 120, 期 4, 页码 611-621出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07605.x
关键词
ADLTE; A-type K plus current; epilepsy; Kv4; 2; LGI1
资金
- US National Institute of Neurological Disorders and Stroke [R21NS070295, R01 NS057444, K02 NS054674-03]
- Nancy Lurie Marks Family Foundation
- Autism Speaks/US National Alliance for Autism Research
- US National Institute of Mental Health NRSA [F32 MH087085]
- Beth Israel Deaconess Medical Center
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 (< 2 h) 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.
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