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: 9.81). 10/2011; 108(41):17076-81. DOI: 10.1073/pnas.1114042108
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Guy Horev, Jul 30, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Psychopharmacology 02/2014; 231(6). DOI:10.1007/s00213-014-3464-y · 3.99 Impact Factor
  • Source
    • "Hyperactive [12] "
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of genetic technologies has led to the identification of several copy number variations (CNVs) in the human genome. Genome rearrangements affect dosage-sensitive gene expression in normal brain development. There is strong evidence associating human psychiatric disorders, especially autism spectrum disorders (ASDs) and schizophrenia to genetic risk factors and accumulated CNV risk loci. Deletions in 1q21, 3q29, 15q13, 17p12, and 22q11, as well as duplications in 16p11, 16p13, and 15q11-13 have been reported as recurrent CNVs in ASD and/or schizophrenia. Chromosome engineering can be a useful technology to reflect human diseases in animal models, especially CNV-based psychiatric disorders. This system, based on the Cre/loxP strategy, uses large chromosome rearrangement such as deletion, duplication, inversion, and translocation. Although it is hard to reflect human pathophysiology in animal models, some aspects of molecular pathways, brain anatomy, cognitive, and behavioral phenotypes can be addressed. Some groups have created animal models of psychiatric disorders, ASD, and schizophrenia, which are based on human CNV. These mouse models display some brain anatomical and behavioral abnormalities, providing insight into human neuropsychiatric disorders that will contribute to novel drug screening for these devastating disorders.
    Neural Plasticity 07/2012; 2012:589524. DOI:10.1155/2012/589524 · 3.60 Impact Factor
  • Source
    • "deletion, 0 in the 16p11.2 duplication, and 1 in the FXS model (Ellegood et al., 2010, 2011; Horev et al., 2011). Contrary to what is found in the ITGβ3, a well replicated finding in human autism is an increase in total brain volume . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The integrinβ3 (ITGβ3) gene has been associated with both autism and the serotonin system. The purpose of this study was to examine the volumetric differences in the brain of an ITGβ3 homozygous knockout mouse model compared with a corresponding wild-type mouse using high resolution magnetic resonance imaging and detailed statistical analyses. The most striking difference found was an 11% reduction in total brain volume. Moreover, 32 different regions were found to have significantly different relative volumes (percentage total brain volume) in the ITGβ3 mouse. A number of interesting differences relevant to autism were discovered including a smaller corpus callosum volume and bilateral decreases in the hippocampus, striatum, and cerebellum. Relative volume increases were also found in the frontal and parieto-temporal lobes as well as in the amygdala. Particularly intriguing were the changes in the lateral wings of the dorsal raphe nuclei since that nucleus is so integral to the development of many different brain regions and the serotonin system in general.
    Frontiers in Psychiatry 04/2012; 3:37. DOI:10.3389/fpsyt.2012.00037
Show more