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Autism‐like behavioral phenotypes in BTBR T+tf/J mice
Abstract
Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self‐grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety‐like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo . The Kmo gene encodes kynurenine 3‐hydroxylase, an enzyme‐regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo , supporting further investigation into the contribution of this polymorphism to autism‐like behavioral phenotypes. Robust and selective social deficits, repetitive self‐grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.
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In the citing paper
“Repetitive behaviours are also often seen in autistic patients and in some mouse models of ASDs34–36.”
From Shank3 mutant mice display autistic-like behaviours and striatal dysfunction (2011) · cites this paper as [34]
In the citing paper
“In contrast to C57Bl6J mice, BTBR mice show no social preference in the test (Fig. 1c, d).20,21”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [20]
In the citing paper
“BTBR T+tf/J (BTBR) is a commercially available inbred strain of mouse that displays behavioral phenotypes relevant to all three diagnostic symptoms of autism (60–62, 64, 66, 68–70, 72, 74–78).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [64]
In the citing paper
“Several naturally occurring inbred strains of mice display behavioral features that recapitulate diagnostic symptoms of neurodevelopmental disorders (59–70).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [64]
In the citing paper
“BTBR engages in low levels of reciprocal social interactions as juveniles and adults, minimal social approach by both males and females, and low levels of ultrasonic vocalizations in response to social olfactory cues and during reciprocal social interactions compared to other standard inbred strains such as C57BL/6J (B6) and FVB (60–62, 64, 66, 68–70, 74, 76–78).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [64]
In the citing paper
“Unlike mouse models based on identified genetic mutations, the background genes responsible for autism-relevant behavioral traits in these inbred strains of mice remain under investigation (64, 83–85).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [64]
In the citing paper
“The BTBR T+ Itpr3tf/J (BTBR) inbred mouse line exhibits the core ASD symptoms, including abnormal social behavior (McFarlane et al., 2008; Scattoni et al., 2008).”
From Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder (2019) · cites this paper as McFarlane et al., 2008
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Self-citation
Metadata
- Authors
- McFarlane, H. G., Kusek, G. K., Yang, M., Phoenix, J. L., Bolivar, V. J., & Crawley, J. N.
- Affiliations
- Kenyon College (US)
- New York State Department of Health (US)
- National Institute of Mental Health (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Crawley, J. N.
- Venue
- Genes, Brain and Behavior
- Publisher
- Wiley
- Published
- 2007-04-27
- Volume
- 7
- Issue
- 2
- Pages
- 152-163
- ISSN
- 1601-183X (ISSN-L)
- 1601-1848
- OpenAlex
- W2071797996
- Cited by
- 812
- References
- 82
- Citations by year
- 2026: 23 · 2025: 36 · 2024: 41 · 2023: 49 · 2022: 52 · 2021: 62 · 2020: 51 · 2019: 44 · 2018: 47 · 2017: 48 · 2016: 63 · 2015: 50 · 2014: 52 · 2013: 42 · 2012: 51
- FWCI
- 8.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Genes Brain & Behavior (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute for Health and Care Research
- National Institutes of Health
- University of North Carolina at Chapel Hill
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- autism spectrum disorder, BTBR T+tf/J mice, social dysfunction, social approach, reciprocal social interaction, social transmission of food preference, KMO, single nucleotide polymorphisms, autism candidate genes, inbred mouse strains, mouse models of autism
- MeSH terms
- Aging, Animals, Autistic Disorder, Circadian Rhythm, Disease Models, Animal, Food Preferences, Mice, Inbred C57BL, Mice, Inbred Strains, National Institute of Mental Health (U.S.), Phenotype, Play and Playthings, Social Behavior, United States, Videotape Recording, Mice
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