Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2011; 108(41):17076-81. DOI: 10.1073/pnas.1114042108
Source: PubMed


Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a "behavior trap" phenotype-a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.

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Available from: Guy Horev
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    • "heterozygous deletions (+/−) were independently generated by the Dolmetsch laboratory at Stanford University and by the Mills group at Cold Spring Harbor Laboratory [31] [65]. Previous findings demonstrated that +/− mice of both lines exhibited substantially reduced body weight, high rate of perinatal mortality , increased spontaneous locomotor activity in a novel home cage environment, and sporadic motor stereotypies [31] [65]. The Dolmetsch line exhibited normal social behaviors in our 3-chambered social approach task, same-sex reciprocal social interactions, and are normal on general health, neurological reflexes, responses to social and non-social odors, motor learning, and anxiety-like behaviors [31] [66]. "
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    ABSTRACT: Mouse models offer indispensable heuristic tools for studying genetic and environmental causes of neuropsychiatric disorders, including autism. Development of useful animal models of complex human behaviors depends not only on extensive knowledge of the human disease, but also on a deep understanding of animal behavior and ethology. Robert and Caroline Blanchard pioneered a number of elegant social paradigms in rodents. Their early work led to systematic delineations of rodent naturalist defensive behaviors, which were proven to be highly useful models of human psychiatric disorders, including fear and anxiety. Their work using the Visible Burrow System to study social stress in rats represented an unprecedented approach to study biological mechanisms of depression. In recent years, their extensive knowledge of mouse behavior and ethology enabled them to quickly become leading figures in the field of behavioral genetics of autism. To commemorate Robert Blanchard's influences on animal models of human psychiatric disorders, here we describe a study conceptualized and led by Mu Yang who was trained as a graduate student in the Blanchard laboratory in the early 2000s. This investigation focuses on social housing in a genetic mouse model of 16p11.2 deletion syndrome. Heterozygous deletions and duplications of a segment containing about 29 genes on human chromosome 16 appear in approximately 0.5-1% of all cases of autism. 16p11.2 deletion syndrome is also associated with intellectual disabilities and speech impairments. Our previous studies showed that a mouse model of 16p11.2 deletion syndrome exhibited deficits in vocalizations and novel object recognition, as compared to wildtype littermate control cagemates. In the spirit of Bob Blanchard's careful attention to the role of social dominance in rodent behaviors, we became interested in the question of whether behavioral outcomes of a mutation differ when mutants are housed in mixed genotype cages, versus housing only mutants together in one group cage, and only wildtype littermates together in another group cage after weaning. 16p11.2 deletion presented a particularly good model organism to investigate this question, because the heterozygotes are smaller than their wildtype littermates, and may therefore become subordinate to their larger cagemates. Wild type and heterozygotes were housed with cagemates of the same genotype (same-genotype cage) or with cagemates of the opposite genotype (mixed-genotype cage). Current results replicated social vocalization and object recognition deficits that we previously found in heterozygotes lived in mixed-genotype cages. In contrast, heterozygotes that lived in same-genotype cages emitted normal numbers of vocalizations during male-female interactions, and displayed normal novel object recognition, indicating that the deletion per se was not sufficient to cause cognitive or social deficits. Social approach, same-sex social interaction, anxiety-related behavior, depression-related behavior, and open field exploration were not different between genotypes, and were not affected by housing in mixed versus in same-genotype cages. These findings suggest that elements of the home cage social environment could interact with genotype to impact aspects of disease phenotypes. Current findings are discussed as potentially reflecting behavioral deficits resulted from social stress, as inspired by a seminal paper by Bob and Caroline Blanchard [1]. Copyright © 2015. Published by Elsevier Inc.
    Preview · Article · Apr 2015 · Physiology & Behavior
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    • "deletion, and 22q11.2 deletion (Horev et al. 2011; Nakatani et al. 2009; Sigurdsson et al. 2010). Cre-loxP was used to generate a balanced duplication and deletion of the chromosomal region analogous to the human 15q11 region in a mouse that parallels the rearrangements and single gene variants causing Angelman and Prader–Willi syndromes (deletion) and ASD (duplication). "
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    ABSTRACT: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by core differences and impairments in social behavioral functioning. There are no approved medications for improving social cognition and behavior in ASD, and the underlying mechanisms needed to discover safer, more effective medications are unclear. In this review, we diagram the basic neurocircuitry governing social behaviors in order to provide a neurobiological framework for the origins of the core social behavioral symptoms of ASD. In addition, we discuss recent technological innovations in research tools that provide unprecedented observation of cellular morphology and activity deep within the intact brain and permit the precise control of discrete brain regions and specific cell types at distinct developmental stages. The use of new technologies to reveal the neural circuits underlying social behavioral impairments associated with ASD is advancing our understanding of the brain changes underlying ASD and enabling the discovery of novel and effective therapeutic interventions.
    Full-text · Article · Feb 2014 · Psychopharmacology
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    • "Several possibilities might explain why copy number losses are detected more often than gains in patients with ID/DD. Horev, et al.21 advocated that deletions exerted a more severe effect than duplications on phenotype, including viability, brain structure, and behavior, in mice. Moreover, Shchelochkov, et al.22 reported that microduplications show milder phenotypes such as subtle dysmorphic facial features, internal organ anomalies, and neuropsychological abnormalities than microdeletions in humans. "
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    ABSTRACT: Purpose This study analyzed and evaluated the demographic, clinical, and cytogenetic data [G-banded karyotyping and array-based comparative genomic hybridization (array CGH)] of patients with unexplained developmental delay or intellectual disability at a single Korean institution. Materials and Methods We collected clinical and cytogenetic data based on retrospective charts at Ajou University Medical Center, Suwon, Korea from April 2008 to March 2012. Results A total of 190 patients were identified. Mean age was 5.1±1.87 years. Array CGH yielded abnormal results in 26 of 190 patients (13.7%). Copy number losses were about two-fold more frequent than gains. A total of 61.5% of all patients had copy number losses. The most common deletion disorders included 22q11.2 deletion syndrome, 15q11.2q12 deletion and 18q deletion syndrome. Copy number gains were identified in 34.6% of patients, and common diseases among these included Potocki-Lupski syndrome, 15q11-13 duplication syndrome and duplication 22q. Abnormal karyotype with normal array CGH results was exhibited in 2.6% of patients; theses included balanced translocation (n=2), inversion (n=2) and low-level mosaicism (n=1). Facial abnormalities (p<0.001) and failure to thrive were (p<0.001) also more frequent in the group of patients with abnormal CGH findings. Conclusion Array CGH is a useful diagnostic tool in clinical settings in patients with developmental delay or intellectual disability combined with facial abnormalities or failure to thrive.
    Full-text · Article · Nov 2013 · Yonsei medical journal
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