Impaired Development of Brain and Behavior in Mice with 16p11.2 Deletion Found in Autism

Background:  

Autism is a genetically determined neurodevelopmental syndrome, yet, its diagnosis is based primarily on behavioral assessment and its etiology remains elusive. A number of copy number variations (CNVs) have been associated with autism. For example, deletion of 16p11.2 occurs in approximately 1% of autism patients, making it one of the most common rearrangements associated with autism. Our recent work indicates that chromosome engineered models of 16p11.2 CNVs have profound brain architectural and behavioral phenotypes, providing the first functional evidence for the causal role of 16p11.2 dosage in autism.

Objectives:  The goal of this study is to gain mechanistic insight into impairments in neurodevelopment and behavior in mice with chromosomal rearrangements corresponding to 16p11.2.

Methods:  We will monitor the behavior of our 16p11.2 CNV models using a video tracking system to characterize motor and feeding deficits in the neonates. We will also characterize the temporal and spatial expression pattern of genes mapping to 16p11.2 by immunohistochemical analyses of brain sections from neonates and embryos.

Results:  We used chromosome engineering to generate mice with the deletion allele (df) as well as those with the reciprocal duplication allele (dp) of the chromosomal region syntenic to human 16p11.2. Our behavioral analyses revealed that df/+ mice differ from controls in multiple measures, with dp/+ mice having reciprocal effects. Using MRI, we identified eight distinct brain regions of df/+ mice with significantly increased volumes. At weaning, df/+ mice are underrepresented, but throughout embryogenesis and immediately after birth, ratios are Mendelian. Further examination revealed that some df/+ neonates lack milk sacs in their stomachs; these mice die within 48 hours of birth. The cause of lethality in half of the df/+ mice is currently unknown. Immunohistochemistry revealed that the expression of MapK3, a gene within 16p11.2 and a major component of ERK signaling, is specifically expressed in neurons that form circuits with the hypothalamus. Our work provides the first functional evidence that 16p11.2 dosage has a profound effect on both behavior and brain anatomy. Furthermore, these findings suggest that the alterations in behavior and brain architecture are due to an impairment of the hypothalamus. The hypothesis that hypothalamic defects link brain anatomy, behavior, and neonatal death may have important implications in autism.

Conclusions:  

Autism is usually diagnosed between 2-3 years of age, but precisely when its earliest signs develop is unknown. Here we use mouse models harboring chromosomal deletions associated with autism to define the window in which defects are first noticed, and to assess how this affects the behavior in the neonate. Mapk3-expressing neural circuits that pass through the hypothalamus are impaired in df/+ mice, and may be responsible for feeding problems and behavioral defects after birth. If these findings extend to humans, it would explain the feeding problems described in patients with 16p11.2 deletions. We believe that by determining the early consequences of 16p11.2 deletions, we will provide the foundation for approaches for early diagnosis and intervention in autism.