Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy

A subset of central glutamatergic synapses are coordinatelypruned and matured by unresolved mechanisms during early postnatal life. We report that human epilepsy gene LGI1, mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We introduced full-length genes encoding (1) ADLTE truncated mutant LGI1 (835delC) and (2) excess wild-type LGI1 proteins into transgenic mice. We discovered that the normal postnatal Kv1 channel-dependent down-regulation of presynaptic release probability and Src kinase-related decrease of postsynaptic NR2B/NR2A ratio were arrested by ADLTE mutant LGI1, and contrastingly, were magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial GABA(A) receptor blockade. Thus, LGI1 represents the first human gene mutated to promote epilepsy through impaired glutamatergic circuit maturation.