LGI1: from zebrafish to human epilepsy.

ABSTRACT

Mutations in the LGI1 gene predispose to autosomal dominant lateral temporal lobe epilepsy, a rare hereditary form with incomplete penetrance and associated with acoustic auras. LGI1 is not a structural component of an ion channel like most epilepsy-related genes, but is a secreted protein. Mutant null mice exhibit early-onset seizures, and electrophysiological analysis shows abnormal synaptic transmission. LGI1 binds to ADAM23 on the presynaptic membrane and ADAM22 on the postsynaptic membrane, further implicating it in regulating the strength of synaptic transmission. Patients with limbic encephalitis show autoantibodies against LGI1 and develop seizures, supporting a role for LGI1 in synapse transmission in the post developmental brain. LGI1, however, also seems to be involved in aspects of neurite development and dendritic pruning, suggesting an additional role in corticogenesis. LGI1 is also involved in cell movement and suppression of dendritic outgrowth in in vitro systems, possibly involving actin cytoskeleton dynamics. Expression patterns in embryonic development correspond to areas of neuronal migration. Loss of LGI1 expression also impacts on myelination of the central and peripheral nervous systems. In zebrafish embryos, knockdown of lgi1a leads to a seizure-like behavior and abnormal brain development, providing a system to study its role in early embryogenesis. Despite being implicated in a role in both synapse transmission and neuronal development, how LGI1 predisposes to epilepsy is still largely unknown. It appears, however, that LGI1 may function differently in a cell context-specific manner, implying a complex involvement in brain development and function that remains to be defined.