A recently discovered human epilepsy gene, LGI1 (leucine-rich glioma-inactivated;mutated to cause human autosomal dominant lateral temporal lobe epilepsy or ADLTE) encodes a protein secreted at glutamate synapses during postnatal glutamate synapse development. Consequently, we hypothesize that LGI1 might promote epilepsy through a novel mechanism, by regulating postnatal glutamate synapse maturation. We propose ADLTE mutant LGI1 acts as a dominant negative to inhibit native LGI1 function and arrest maturation. To directly address our hypothesis and contrast the functional effects of epilepsy-associated mutant LGI1 with those of excess wild-type LGI1 on native neural circuits, we created transgenic mice using bacterial artificial chromosomes (BAC) carrying a large 226 kb fragment of mouse genomic DNA encoding the full-length LGI1 gene. The ADLTE 835delC mutation introduced a premature translational stop codon to generate a truncated LGI1 protein. The full-length gene BAC transgenic approach is important to maintain native patterns of gene expression and transcript splicing in order to assess the genes effects on the glutamate synapse development process in vivo. LGI1 is heavily expressed presynaptically at medial entorhinal cortex perforant pathway glutamate synapses innervating dentate granule neurons (MPP- dentate) and also separately in a synapse targeting thalamus. Our overall goal is to define the cellular basis for human ADLT epilepsy. We specifically test whether excess LGI1 magnifies and mutant LGI1 blocks maturation of the following glutamate synapse properties during the postnatal periods when it becomes expressed and throughout adulthood in dentate gyrus and thalamus. We examine: 1) presynaptic glutamate release down-regulation and role of Kv1.1 K+ channel activity;2) postsynaptic NR2B NMDA receptor current and synaptic plasticity down-regulation, PSD95-Src complex formation, and the role of Src kinase activity;and 3) dendrite branch (e.g., dentate) and axon input (e.g., thalamus) pruning. This murine model of human ADLT epilepsy could link a novel human epilepsy gene to the arrest of glutamate synapse maturation and potentially defining a cellular basis for human seizure disorders beyond ADLTE.
This project seeks to identify the cellular basis of the inherited human epilepsy disorder caused by mutations in LGI1, a secreted synaptic protein. The results should provide new insights into the cellular and molecular basis of human epilepsy, and help identify new potential therapeutic targets to treat this common brain disorder.
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| Kasten, Michael R; Anderson, Matthew P (2015) Self-regulation of adult thalamocortical neurons. J Neurophysiol 114:323-31 |
| Boillot, Morgane; Huneau, Clément; Marsan, Elise et al. (2014) Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures. Brain 137:2984-96 |
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| Smith, Stephen E P; Xu, Lin; Kasten, Michael R et al. (2012) Mutant LGI1 inhibits seizure-induced trafficking of Kv4.2 potassium channels. J Neurochem 120:611-21 |
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