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

Authors

  • Stephen E. P. Smith,

    1. Departments of Neurology and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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  • Lin Xu,

    1. Departments of Neurology and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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  • Michael R. Kasten,

    1. Departments of Neurology and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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  • Matthew P. Anderson

    1. Departments of Neurology and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
    2. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA
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Address correspondence and reprint requests to Matthew P. Anderson, MD, PhD, Departments of Neurology and Pathology, and Program in Neuroscience, Beth Israel Deaconess Medical Center, Center for Life Science, 330 Brookline Ave, E/CLS-717, Boston, MA 02215, USA.E-mail: matthew_anderson@bidmc.harvard.edu

Abstract

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.

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