Fmr1 and Nlgn3 knockout rats: novel tools for investigating autism spectrum disorders.
Animal models are critical for gaining insights into autism spectrum disorder (ASD). Despite their apparent advantages to mice for neural studies, rats have not been widely used for disorders of the human CNS, such as ASD, for the lack of convenient genome manipulation tools. Here we describe two of the first transgenic rat models for ASD, developed using zinc-finger nuclease (ZFN) methodologies, and their initial behavioral assessment using a rapid juvenile test battery. A syndromic and nonsyndromic rat model for ASD were created as two separate knockout rat lines with heritable disruptions in the genes encoding Fragile X mental retardation protein (FMRP) and Neuroligin3 (NLGN3). FMRP, a protein with numerous proposed functions including regulation of mRNA and synaptic protein synthesis, and NLGN3, a member of the neuroligin synaptic cell-adhesion protein family, have been implicated in human ASD. Juvenile subjects from both knockout rat lines exhibited abnormalities in ASD-relevant phenotypes including juvenile play, perseverative behaviors, and sensorimotor gating. These data provide important first evidence regarding the utility of rats as genetic models for investigating ASD-relevant genes.
Department of Molecular and Human Genetics, Baylor College of Medicine.
Shannon M
SM
Hamilton
Department of Molecular and Human Genetics, Baylor College of Medicine.
Jennie R
JR
Green
Department of Molecular and Human Genetics, Baylor College of Medicine.
Surabi
S
Veeraragavan
Department of Molecular and Human Genetics, Baylor College of Medicine.
Lisa
L
Yuva
SAGE Labs.
Aaron
A
McCoy
SAGE Labs.
Yumei
Y
Wu
SAGE Labs.
Joe
J
Warren
SAGE Labs.
Lara
L
Little
SAGE Labs.
Diana
D
Ji
SAGE Labs.
Xiaoxia
X
Cui
SAGE Labs.
Edward
E
Weinstein
Department of Molecular and Human Genetics, Baylor College of Medicine.
Richard
R
Paylor
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000523:psychology; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012919:Social Behavior
D015816:Cell Adhesion Molecules, Neuronal; D051860:Fragile X Messenger Ribonucleoprotein 1; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C497685:Fmr1 protein, rat; C098004:neuroligin 3