Abstracts

Recent studies have found epilepsy-associated mutations in non-ion channel genes. LGI1, a secreted protein of unknown function, was found to be mutated in patients with autosomal dominant lateral temporal lobe epilepsy (ADLTE). To investigate the functional effects of this protein on native neural circuits, we developed methods to study wild-type and mutant LGI1 protein in living brain tissue., Transgenic mice were created using a full-length LGI1 gene engineered to contain the epilepsy-associated LGI1 gene mutations. We also created transgenic mice using the wild-type, full-length LGI1 gene. In order to measure the effect of this mutant protein on neuron excitability and synaptic communication, we prepared acute brain slices from adult LGI1 transgenic and control mice and compared the electrophysiological properties of individual neurons. Because ADLTE is characterized by auditory hallucinations during seizures, we studied neurons in a second order thalamic nucleus that relays auditory sensation to the cortex, the dorsal medial geniculate nucleus (DMGn)., Mutant LGI1 transgene increased the intrinsic excitability of DMGn thalamic neurons. Mutant LGI1 transgene also increased phosphorylation of a number of protein kinases., These findings support our current hypothesis that mutant LGI1 causes epilepsy through a unique mechanism involving altered signal transduction., (Supported by: Funded by National Institute of Neurologic Disease (MPA), Burrough Wellcome Fund Career Award (MPA), and Beth Israel Deaconess Medical Center.)