title: Genetic interactions among cortical malformation genes that influence susceptibility to convulsions in C. elegans.
abstract: Epilepsy is estimated to affect 1-2% of the world population, yet remains poorly understood at a molecular level. We have previously established the roundworm Caenorhabditis elegans as a model for investigating genetic susceptibilities to seizure-like convulsions in vivo. Here we investigate the behavioral consequences of decreasing the activity of nematode gene homologs within the LIS1 pathway that are associated with a human cortical malformation termed lissencephaly. Bioinformatic analysis revealed the nud-2 gene, encoding the worm homolog of mammalian effectors of LIS1, termed NDE1 and NDEL1. Phenotypic analysis of animals targeted by RNA interference (RNAi) was performed using a pentylenetetrazole (PTZ) exposure paradigm to induce convulsions. Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5, and CDKA-1) exhibited significant convulsions following PTZ and RNAi treatment. Strains harboring fluorescent markers for GABAergic neuronal architecture and synaptic vesicle trafficking were employed to discern putative mechanisms accounting for observed convulsion behaviors. We found that depletion of LIS1 pathway components resulted in defective GABA synaptic vesicle trafficking. We also utilized combinations of specific genetic backgrounds to create a sensitized state for convulsion susceptibility and discovered that convulsion effects were significantly enhanced when LIS-1 and other pathway components were compromised within the same animals. Thus, interactions among gene products with LIS-1 may mediate intrinsic thresholds of neuronal synchrony.
authors.affiliation: Department of Biological Sciences, The University of Alabama, Box 870344, Tuscaloosa, AL 35487-0344, USA.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Locke
authors.forename: Shelli N
authors.initials: SN
authors.lastname: Williams
authors.forename: Erich M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D019295:Computational Biology / Q000379:methods; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D008845:Microinjections / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010433:Pentylenetetrazole; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012640:Seizures / Q000139:chemically induced / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D010433:Pentylenetetrazole