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Mutant LGI1 inhibits seizure‐induced trafficking of Kv4.2 potassium channels
Author(s) -
Smith Stephen E. P.,
Xu Lin,
Kasten Michael R.,
Anderson Matthew P.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07605.x
Subject(s) - neuroscience , excitatory postsynaptic potential , glutamatergic , epilepsy , biology , glutamate receptor , neurotransmission , potassium channel , biophysics , inhibitory postsynaptic potential , receptor , genetics
J. Neurochem. (2012) 120 , 611–621. 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 (< 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.