Behavioral Profiles of Mouse Models for Autism Spectrum Disorders
Elodie Ey, Claire S. Leblond, and Thomas Bourgeron
Autism spectrum disorders (ASD) are characterized by impairments in reciprocal social communication, and stereotyped verbal and non-verbal behaviors. ASD affect more than 1 person on 150 worldwide and in approximately 10–25 % of cases, a genetic mutation associated with the condition can be identified. Recently, genetic mutations altering connections between nerve cells (the so–called synapses), cellular/synaptic growth rate or regulation of excitatory were identified in patients with ASD. Following these genetic findings, mouse models carrying mutations similar to those identified in patients have been generated. These models offer the possibility to investigate in vivo the physiological and behavioral consequences of the mutations. Here, we review the existing data on the phenotypes of mice carrying mutations in genes associated with ASD. The diversity and complexity of the phenotype of these mouse models reflect the broad range of phenotypes observed in patients with ASD. Remarkably, results from approaches to reverse the phenotype (e.g., modulation of gene expression, administration of pharmacological and non-pharmacological substances, enriched environment) are encouraging since some behavioral alterations could be reversed even when treatment was performed on adult mice. It is therefore likely that studies of these animal models will increase our understanding of the brain alterations associated with ASD and promote the development of knowledge-based therapies. © 2011 INSAR/Wiley Periodicals, Inc.
Article Citation: Austism Res 2011, 4: 5–16. DOI: 10.1002/aur.175
Social Peers Rescue Autism-Relevant Sociability Deficits in Adolescent Mice
Mu Yang, Kayla Perry, Michael D. Weber, Adam M. Katz, and Jacqueline N. Crawley
Limited reciprocal social interactions are central to the diagnosis of autism. Behavioral intervention programs are effective in improving social and communication skills in children with autism. We are employing mouse models to understand the individual components of behavioral interventions which effectively improve social interactions. BTBR T+tf/J (BTBR) is an inbred strain of mice that exhibits multiple social deficits, unusual vocalizations, and high levels of repetitive behaviors, which are relevant to all three diagnostic symptom categories of autism. C57BL/6J (B6) is an inbred strain of mice that exhibits high sociability and low repetitive behaviors. We reasoned that these mouse strains with low versus high social interactions might be useful for evaluating social peer enrichment as a behavioral intervention during adolescence. Juvenile BTBR and B6 of the same sex were placed in a same home cage and lived together as cagemates until they reached young adulthood. The two control groups were juvenile B6 housed together, and juvenile BTBR housed together. B6 controls that lived with B6 cagemates showed their strain-typical high sociability. BTBR controls that lived with BTBR cagemates showed their strain-typical low sociability. Remarkably, BTBR that shared home cages with B6 showed high sociability as young adults. Peer rearing for either 20 days or 40 days were equally effective. These results from a robust mouse model of autism support the strategy of early behavioral intervention for treating the social domain in autism spectrum disorders, including beneficial interactions with social peers. © 2011 INSAR/Wiley Periodicals, Inc.
Article Citation: Austism Res 2011, 4: 17–27. DOI: 10.1002/aur.163
Haploinsufficiency of Gtf2i, a Gene Deleted in Williams Syndrome, Leads to Increases in Social Interactions
Takeshi Sakurai, Nathan P. Dorr, Nagahide Takahashi, L. Alison McInnes, Gregory A. Elder, and Joseph D. Buxbaum
Social behavioral deficits are one of the hallmarks of autism spectrum disorders (ASD), and understanding the genes and brain circuitry underlying social behavior is crucial to understanding ASD. Williams-Beuren syndrome (WBS) is a neurodevelopmental syndrome caused by a loss of one copy of a chromosome region containing about 28 genes. One aspect of the unique neurocognitive profile of WBS patients is striking hypersociability, which presents as overfriendliness even to strangers. Careful studies of individuals with atypical deletions have implicated a gene called GTF2I in these altered social behaviors. We have developed a mouse model that has a disruption in one copy of this gene and characterized this model behaviorally. The animals show no alterations in learning and memory, but show increased sociability to unfamiliar mice, reminiscent of the hypersociability associated with WBS patients. Our study suggests that a loss of one functional copy of GTF2I may contribute to hypersociability in humans and that GTF2I may play an important role in the development of circuitry underlying typical social behaviors in humans. © 2011 INSAR/Wiley Periodicals, Inc.
Article Citation: Austism Res 2011, 4: 28–39. DOI: 10.1002/aur.169
Modifying Behavioral Phenotypes in Fmr1 KO Mice: Genetic Background Differences Reveal Autistic-Like Responses
Corinne M. Spencer, Olga Alekseyenko, Shannon M. Hamilton, Alexia M. Thomas, Ekaterina Serysheva, Lisa A. Yuva-Paylor, and Richard Paylor
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in humans. In addition to cognitive impairment, patients may exhibit hyperactivity, attention deficits, social difficulties and anxiety, and autistic-like behaviors. The degree to which patients display these behaviors varies considerably and is influenced by family history, suggesting that other genes play a role in the expression of behaviors in FXS. Several studies have examined behavior in a mouse model of FXS in which the Fmr1 gene has been knocked-out. To gain a better understanding of the impact of differences in other genes on the behavior of Fmr1 KO mice we generated multiple types of mice that all had the same Fmr1 mutation, but that differed in the make-up of the other background genes. Our results clearly indicate that many behavioral responses are influenced not only by the Fmr1 mutation, but also by the composition of the remaining background genes. Interestingly, it appears that autistic-like traits in Fmr1 KO mice is significantly affected by other background genes and primarily observed in a particular genetic background. Our approach has allowed us to identify improved mouse models for different behavioral symptoms present in FXS including autistic-like traits. © 2011 INSAR/Wiley Periodicals, Inc.
Article Citation: Austism Res 2011, 4: 40–56. DOI: 10.1002/aur.168
Absence of Preference for Social Novelty and Increased Grooming in Integrin β3 Knockout Mice: Initial Studies and Future Directions
Michelle D. Carter, Charisma R. Shah, Christopher L. Muller, Jacqueline N. Crawley, Ana M. D. Carneiro, and Jeremy Veenstra-VanderWeele
Increased levels of serotonin in the blood are found in about 30% of children with autism spectrum disorder (ASD). In the blood, serotonin is contained almost entirely in platelets. Blood serotonin levels themselves are associated with variation in the integrin β3 gene. The integrin β3 protein interacts with the serotonin transporter (SERT), which controls the uptake of serotonin into the platelet. Multiple studies have now reported an association between variation in the integrin β3 and serotonin transporter genes and autism. We compared mice with decreased or absent levels of the integrin β3 gene with normal mice in behavioral tasks relevant to ASD. These mice showed normal levels of activity and anxiety-like behavior. Similarly, they were able to smell normally and recall familiar odors. When offered the choice, mice lacking integrin β3 preferred to spend time near a novel mouse instead of a novel object, but they did not show the normal preference for a novel mouse over a familiar mouse, suggesting a change in social recognition or social function. Additionally, mice lacking integrin β3 showed increased grooming behavior in novel environments. These preliminary studies reveal altered social and repetitive behavior in these mice, which suggests that the integrin β3 subunit may be involved in brain systems relevant to ASD. Further work is needed to fully characterize these behavioral changes and the underlying brain mechanisms. © 2011 INSAR/Wiley Periodicals, Inc.
Article Citation: Austism Res 2011, 4: 57–67. DOI: 10.1002/aur.180
The Autism Risk Genes MET and PLAUR Differentially Impact Cortical Development
Kathie L. Eagleson, Daniel B. Campbell, Barbara L. Thompson, Mica Y. Bergman, and Pat Levitt
Over the past decade, candidate genes that increase risk for autism spectrum disorder (ASD) have been identified. However, little is known about how these findings of increased genetic risk translate into the disruptions in brain development that cause the behaviors that are characteristic of ASD. One idea has been that risk genes for ASD cause an imbalance in excitation and inhibition in circuits of the cerebral cortex, the structure that controls complex functions. Imbalances would lead to problems in information flow and, in extreme cases, cause seizure disorder, a common medical condition in children with ASD. Our laboratory has identified changes in the DNA sequence of two genes, MET and PLAUR, that are associated with increased risk for ASD. Our previous work suggested that both of these genes were involved in controlling inhibitory neuron development. Through the use of genetic mouse models and biochemical and molecular analysis, we show that Met can only be involved directly in the development and function of excitatory neurons. In contrast, PLAUR modulates the maturation of inhibitory neurons, which act as a brake on projection neuron function. We also find, however, that under certain environmental conditions, Met can be activated in inhibitory neurons and therefore could influence the development of this cell type under certain pathological conditions. Our data support a popular hypothesis that a disruption in the balance of function between excitatory projection neurons and inhibitory interneurons underlies, in part, altered cortical architecture in ASD. © 2011 INSAR/Wiley Periodicals, Inc.
Article Citation: Austism Res 2011, 4: 68–83. DOI: 10.1002/aur.172