Haploinsufficiency of LIS1 often results in isolated lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS), neurological disorders characterized by a smooth cerebral cortex and intractable epileptic convulsions long associated with neuronal migration. Notably, MDS is generally more severe than ILS due to an additional deletion of a LIS1-localizing gene, 14-3-3epsilon (Ywhae), from the 17p13.3 region. Along with 14-3-3epsilon, other genes have been shown to function in the same pathway as LIS1, including Ndel1 (NUDEL), cytoplasmic dynein and kinesin subunits,
cdk5,
p35, and DCX. Accordingly, we have demonstrated that
lis-1 (
pnm-1) mutants, kinesin (
klp-1) mutants, and dynein (
dhc-1) RNAi escapers can exhibit epileptic-like convulsions, as evidenced by repeated contraction of their anterior regions when exposed to relatively low concentrations of pentylenetetrazole (PTZ), an antagonist of GABAergic reception. Moreover, such worms do not have overt neuronal migration defects. Instead, LIS-1 pathway defective worms expressing
unc-25::SNB-1::GFP reproducibly exhibit a clustering of synaptic vesicles at the presynaptic termini, implicating aberrant release of GABA as potentially causative for the convulsive phenotype.To determine if other genes functioning in the LIS1 pathway regulate the trafficking of synaptic vesicles and neuronal excitability, we identified putative worm orthologs of LIS1 pathway members through various bioinformatics resources, such as CarpeDB (www.carpedb.ua.edu), and targeted them for phenotypic knockdown by RNAi feeding. Indeed, we observed significant changes in the distribution of
unc-25::SNB-1::GFP at GABAergic synapses in multiple RNAi targets, including
kap-1,
klp-1,
klp-11,
klp-3,
dli-1, and R11A5.2 (NUDE). We hypothesize that diminished rates of GABA release may contribute to postsynaptic overexcitation, which, like in LIS-1 pathway defective worms, is manifested as enhanced susceptibility to PTZ-induced convulsions. Although RNAi against worm LIS-1 pathway members in an N2 background generated slightly enhanced susceptibilities to PTZ-induced convulsions, similar methods with
pnm-1 and
unc-25 backgrounds produced substantially greater numbers of worms exhibiting epileptic-like activity when coupled to increasing PTZ concentrations. These findings illustrate the potential evolutionary conservation of LIS1 pathway function between C. elegans and humans, while implicating cytoskeletal genes as playing a role in the epileptic consequences of lissencephaly.