Scientists at Emory University School of Medicine have created a mouse model of human 3q29 deletion syndrome, which is expected to provide insights into the genetic underpinnings of both schizophrenia and autism spectrum disorder.

In 3q29 deletion syndrome, a stretch of DNA containing several genes is missing from one of a child’s chromosomes. The deletion usually occurs spontaneously rather than being inherited. Affected individuals have a higher risk of developing intellectual disability, schizophrenia, and autism spectrum disorder. 3q29 deletion is one of the strongest genetic risk factors for schizophrenia, and the Emory researchers see investigating it as a way of unraveling schizophrenia’s biological and genetic complexity.

The results were published in Molecular Psychiatry.

“We see these mice as useful tools for understanding the parts of the brain whose development is perturbed by 3q29 deletion, and how it affects males and females differently,” says Jennifer Mulle, PhD, assistant professor of human genetics. “They are also a starting point for dissecting individual genes within the 3q29 deletion.”

Working with clinicians and psychologists at Marcus Autism Center, Mulle is leading an ongoing study of 3q29 deletion’s effects in humans, and observations from the mice are expected to inform these efforts. (More about Mulle here.)

The mutant mice, created with CRISPR-Cas9 technology, display behavioral changes that correspond to some symptoms of related neuropsychiatric disorders. Some of the effects of 3q29 deletion, such as impaired social interaction and spatial memory defects, appear only in male mice. Normal mice will prefer to interact with a new acquaintance mouse more than an empty cup, but male mutant mice show no preference. They also have deficits in the Morris water maze test, a standard test of spatial memory in animals.

Overall, mutant mice have smaller brains and reduced body weight compared with wild-type mice. Both male and female mutant mice display increased startle in response to noise; the effect is stronger in females. This may correspond to reported hypersensitivity to acoustic stimuli observed in autism spectrum disorder, the authors write. However, the mutant mice have normal prepulse inhibition, meaning that they can distinguish sensory stimuli arriving close together in time in a normal way. Reduced prepulse inhibition is a well-documented phenomenon in people with schizophrenia.

The Emory researchers also compared the 3q29 deletion mice with mice containing a mutations in one of the genes found within the deletion, DLG1. This gene had previously been linked to schizophrenia in human genetic studies. However, the behavioral effects of deleting just one copy of DLG1 was minimal, compared with the entire 3q29 deletion.

The first author of the paper is postdoctoral fellow Timothy Rutkowski. Additional Emory authors include Jason Schroeder, Michael Epstein, Gary Bassell, Stephen Warren, David Weinshenker and Tamara Caspary.

The research was supported by the National Institute of General Medical Sciences (R01GM097331), the National Institute of Mental Health (R56MH116994, R01MH110701) and the Georgia Clinical and Translational Science Alliance (UL1TR002378).