Social approach in genetically engineered mouse lines relevant to autism.
Profound impairment in social interaction is a core symptom of autism, a severe neurodevelopmental disorder. Deficits can include a lack of interest in social contact and low levels of approach and proximity to other children. In this study, a three-chambered choice task was used to evaluate sociability and social novelty preference in five lines of mice with mutations in genes implicated in autism spectrum disorders. Fmr1(tm1Cgr/Y)(Fmr1(-/y)) mice represent a model for fragile X, a mental retardation syndrome that is partially comorbid with autism. We tested Fmr1(-/y)mice on two genetic backgrounds, C57BL/6J and FVB/N-129/OlaHsd (FVB/129). Targeted disruption of Fmr1 resulted in low sociability on one measure, but only when the mutation was expressed on FVB/129. Autism has been associated with altered serotonin levels and polymorphisms in SLC6A4 (SERT), the serotonin transporter gene. Male mice with targeted disruption of Slc6a4 displayed significantly less sociability than wild-type controls. Mice with conditional overexpression of Igf-1 (insulin-like growth factor-1) offered a model for brain overgrowth associated with autism. Igf-1 transgenic mice engaged in levels of social approach similar to wild-type controls. Targeted disruption in other genes of interest, En2 (engrailed-2) and Dhcr7, was carried on genetic backgrounds that showed low levels of exploration in the choice task, precluding meaningful interpretations of social behavior scores. Overall, results show that loss of Fmr1 or Slc6a4 gene function can lead to deficits in sociability. Findings from the fragile X model suggest that the FVB/129 background confers enhanced susceptibility to consequences of Fmr1 mutation on social approach.
Moy
S S
SS
Neurodevelopmental Disorders Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. ssmoy@med.unc.edu
Nadler
J J
JJ
Young
N B
NB
Nonneman
R J
RJ
Grossman
A W
AW
Murphy
D L
DL
D'Ercole
A J
AJ
Crawley
J N
JN
Magnuson
T R
TR
Lauder
J M
JM
D000818:Animals; D001007:Anxiety / Q000523:psychology; D001321:Autistic Disorder / Q000235:genetics* / Q000523:psychology*; D001522:Behavior, Animal / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005508:Food Deprivation / Q000502:physiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005818:Genetic Engineering; D018398:Homeodomain Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics* / Q000523:psychology*; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D004856:Postural Balance / Q000502:physiology; D011247:Pregnancy; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D012727:Sex Characteristics; D012903:Smell / Q000235:genetics / Q000502:physiology; D012919:Social Behavior; D000099266:Engrailed 2 Protein
D051860:Fragile X Messenger Ribonucleoprotein 1; D018398:Homeodomain Proteins; D007334:Insulin-Like Growth Factor I; D009419:Nerve Tissue Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050486:Serotonin Plasma Membrane Transport Proteins; D000099266:Engrailed 2 Protein; C497684:Fmr1 protein, mouse; C493231:Slc6a4 protein, mouse; C019995:7-dehydrocholesterol reductase