Thus, although the role of LGI1 in seizure development is now well established, the underlying molecular mechanisms behind this phenotype are still largely unknown. With the intent of developing a more tractable, vertebrate model to study the function of LGI1, we used morpholino knockdown strategies to inactivate LGI1 orthologs in developing zebrafish embryos. The lgi1a morphant fish show a distinct seizure-like behavior which was similar to that induced as a result of treatment with epilepsy-inducing drugs. The lgi1a knockdown fish also showed developmental abnormalities, including abnormal tail shape, SAR131675 smaller eyes and reduced brain mass accompanied by increased apoptosis. Evidence for abnormal brain development has also been suggested in imaging studies of ADPEAF patients, possibly indicating a role for LGI1 in brain development. These observations are consistent with those from gene expression studies using cell culture systems implicating LGI1 in axon guidance pathways. The zebrafish knock down model, therefore, provides a potentially valuable model to study the role of LGI1 in early development of the brain and its relationship with the underlying mechanism of seizure induction. The zebrafish genome has undergone a partial duplication during evolution, resulting in two different paralogs for many mammalian genes. The LGI1 gene was part of that duplication, generating the zebrafish lgi1a and lgi1b genes. In situ hybridization analysis of lgi1a/b gene expression demonstrated a distinct, albeit overlapping, expression pattern for each homolog, suggesting a concomitant subfunctionalization. The seizure-like phenotype and developmental abnormalities described by Teng et al, resulted from the knockdown of the lgi1a gene. We have now generated knockdown morphants for the lgi1b gene which, consistent with the suggested subfunctionalization of these genes, demonstrate a very different phenotype. These morphants do not develop the overt seizure-like behavior seen in the lgi1a morphants. The lgi1b morphants, however, display a hypersensitivity to the epilepsy-inducing drug PTZ, as also shown for the lgi1a morphants. The lgi1b morphants also showed delayed overall development and smaller eyes and brains, as seen in the lgi1a morphants, with associated increased apoptosis. The main difference in gross phenotype involved the significantly increased ventricle size in the lgi1b morphants. Thus, the different phenotypes seen in the lgi1a and lgi1b morphants provides the opportunity to dissect the function of the lgi1 paralogs in zebrafish. The knockdown of lgi1a led to the development of a seizure-like behavior as well as developmental abnormalities involving the brain and eyes and, at high doses of morpholino, to abnormalities of the tail. The lgi1b morphants also showed abnormalities of the development of the eye and brain but did not show abnormalities of the tail and did not show seizure-like behavior, although both morphants were sensitized to PTZinduced hyperactivity. The unique feature of the lgi1b morphant was the pronounced hydrocephalus.