title: Knockdown of zebrafish Lgi1a results in abnormal development, brain defects and a seizure-like behavioral phenotype.
abstract: Epilepsy is a common disorder, typified by recurrent seizures with underlying neurological disorders or disease. Approximately one-third of patients are unresponsive to currently available therapies. Thus, a deeper understanding of the genetics and etiology of epilepsy is needed to advance the development of new therapies. Previously, treatment of zebrafish with epilepsy-inducing pharmacological agents was shown to result in a seizure-like phenotype, suggesting that fish provide a tractable model to understand the function of epilepsy-predisposing genes. Here, we report the first model of genetically linked epilepsy in zebrafish and provide an initial characterization of the behavioral and neurological phenotypes associated with morpholino (MO) knockdown of leucine-rich, glioma-inactivated 1a (lgi1a) expression. Mutations in the LGI1 gene in humans have been shown to predispose to a subtype of autosomal dominant epilepsy. Low-dose Lgi1a MO knockdown fish (morphants) appear morphologically normal but are sensitized to epilepsy-inducing drugs. High-dose Lgi1a morphants have morphological defects which persist into adult stages that are typified by smaller brains and eyes and abnormalities in tail shape, and display hyperactive swimming behaviors. Increased apoptosis was observed throughout the central nervous system of high-dose morphant fish, accounting for the size reduction of neural tissues. These observations demonstrate that zebrafish can be exploited to dissect the embryonic function(s) of genes known to predispose to seizure-like behavior in humans, and offer potential insight into the relationship between developmental neurobiological abnormalities and seizure.
authors.affiliation: MCG Cancer Center, Medical College of Georgia, School of Medicine, 1120 15th Street, Augusta, GA 30912, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
authors.forename: Xiayang
authors.initials: X
authors.lastname: Xie
authors.forename: Steven
authors.initials: S
authors.lastname: Walker
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Rempala
authors.forename: David J
authors.initials: DJ
authors.lastname: Kozlowski
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Mumm
authors.forename: John K
authors.initials: JK
authors.lastname: Cowell
mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005123:Eye / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D012640:Seizures / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000002:abnormalities / Q000235:genetics* / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: C555909:Lgi1a protein, zebrafish; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D029961:Zebrafish Proteins
references.citation: Epilepsia. 2007 Jun;48(6):1151-7
references.pmid: 17521353
references.citation: Mol Biol Evol. 2005 Nov;22(11):2209-16
references.pmid: 16014869
references.citation: Oncogene. 1998 Dec 3;17(22):2873-81
references.pmid: 9879993
references.citation: MMWR Surveill Summ. 2008 Aug 8;57(6):1-20
references.pmid: 18685554
references.citation: Mamm Genome. 2007 May;18(5):328-37
references.pmid: 17565425
references.citation: Nat Genet. 2002 Mar;30(3):335-41
references.pmid: 11810107
references.citation: Annu Rev Neurosci. 2003;26:599-625
references.pmid: 14527270
references.citation: Hum Mol Genet. 2006 Dec 1;15(23):3436-45
references.pmid: 17067999
references.citation: Epilepsia. 2005;46 Suppl 10:59-60
references.pmid: 16359474
references.citation: Genomics. 2010 Feb;95(2):93-100
references.pmid: 19835947
references.citation: Hum Mol Genet. 2010 May 1;19(9):1702-11
references.pmid: 20130004
references.citation: J Pharmacol Toxicol Methods. 2008 May-Jun;57(3):176-87
references.pmid: 18337127
references.citation: Science. 2006 Sep 22;313(5794):1792-5
references.pmid: 16990550
references.citation: Neurology. 2007 Sep 18;69(12):1298-300
references.pmid: 17875918
references.citation: Hum Mutat. 2009 Apr;30(4):530-6
references.pmid: 19191227
references.citation: Neuron. 2006 Mar 2;49(5):697-706
references.pmid: 16504945
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3799-804
references.pmid: 20133599
references.citation: Ann Neurol. 1999 Feb;45(2):182-8
references.pmid: 9989620
references.citation: Hum Mol Genet. 2005 Jun 15;14(12):1613-20
references.pmid: 15857855
references.citation: Nat Med. 2009 Oct;15(10):1208-14
references.pmid: 19701204
references.citation: Exp Neurol. 2008 Jun;211(2):480-8
references.pmid: 18402939
references.citation: Development. 2008 May;135(10):1735-43
references.pmid: 18403413
references.citation: Nat Rev Genet. 2007 May;8(5):353-67
references.pmid: 17440532
references.citation: Nat Genet. 1995 May;10(1):56-60
references.pmid: 7647791
references.citation: Dev Dyn. 1995 Jul;203(3):253-310
references.pmid: 8589427
references.citation: Hum Mol Genet. 2009 Apr 15;18(R1):R107-12
references.pmid: 19297397
references.citation: Am J Med Genet. 2001 Summer;106(2):146-59
references.pmid: 11579435
references.citation: Arch Neurol. 2003 Nov;60(11):1546-51
references.pmid: 14623726
references.citation: Biochem Biophys Res Commun. 2007 Jun 29;358(2):521-7
references.pmid: 17493584
references.citation: Neuroscience. 2005;131(3):759-68
references.pmid: 15730879
references.citation: Epilepsia. 2003 Oct;44(10):1289-97
references.pmid: 14510822
references.citation: Epilepsy Res. 2007 Jun;75(1):18-28
references.pmid: 17485198
references.citation: Curr Opin Neurol. 2004 Apr;17(2):147-53
references.pmid: 15021241