Jacobsen syndrome (JBS) is a rare inherited disorder characterized by a chromosomal flaw, which causes nearly half of children born with the disorder to also suffer autism-like symptoms in addition to the other more common ones. To understand what connects the genetic defect to such brain and behavioral abnormalities, UC San Diego School of Medicine researchers bred a mouse with both the usual symptoms of JBS and those of autism. Following their study, the researchers say a tranquilizer normally prescribed for seizures and anxiety might reduce autistic symptoms in JBS patients.

Roughly one in every 100,000 children is born with Jacobsen, and missing just a portion of one copy of chromosome 11. Patients commonly suffer intellectual disability, a deformity of the heart, and characteristic abnormalities in their facial structure, among other symptoms. Researchers had previously identified several possible genes responsible for each symptom, and, most recently, one scientific team suggested the absence of four particular genes might cause the autism-like symptoms half of all JBS patients experience.

Among the four culprits, PX-RICS seemed the most promising for research. So, Dr. Paul Grossfeld, a clinical professor of pediatrics, contacted researchers at the University of Tokyo who, though unaware of a possible link to Jacobsen, had already begun studying PX-RICS. Together, the scientists bred a mouse lacking this key gene.

Behavior and the Brain

Having created this new breed, the researchers performed several tests on the mice to measure common autism symptoms, including antisocial behavior, repetitive activity, and an unswerving loyalty to routines. Compared to normal mice, those lacking PX-RICS spent less time sniffing each other nose-to-nose and huddling together. They were also more apathetic or avoidant when other mice were nearby. PX-RICS-deficient mice spent more than twice as much time as ordinary mice on repetitive behaviors, including self-grooming and digging. Plus, they were less adaptable in new situations and closely adhered to their established habits.

After exploring the behavior of these unique mice, the researchers studied their brains. Here, they discovered the PX-RICS-deficient mice also lacked a GABA receptor protein known to be crucial for normal cognitive function. “Recently, dysfunctional GABA signaling has been increasingly reported to be associated with autism spectrum disorders,” Grossfeld and his colleagues wrote.

GABA, a neurotransmitter, plays a role in reducing the “excitability” of neurons throughout the nervous system. Essentially, GABA modifies electrical activity in the brain, tamping down abnormal activity when necessary. In fact, past evidence suggests an imbalance between the excitation and inhibition of neurons in some regions of the brain may cause the behavioral and cognitive symptoms associated with several psychiatric diseases — including autism.

Because the PX-RICS-deficient mice lacked a GABA protein, the researchers decided to test clonazepam, a commonly used anti-anxiety drug, as a possible treatment for reducing the autism-like symptoms in the mice with Jacobsen syndrome. Clonazepam works by binding to certain GABA receptors and boosting the effects of the essential neurotransmitter. After treating the PX-RICS-deficient mice with low doses of clonazepam, the researchers observed nearly normal social behavior, improvements in learning performance, and increased adaptability — where the mice were less likely to cling to their established routines.

Going forward, the researchers hope to conduct a small clinical trial on people with Jacobsen syndrome and autism symptoms in order to see if clonazepam provides beneficial effects. Because PX-RICS is known to interact with more than 60 proteins, the scientists suggest further research to understand more about the function of this gene. They also believe their work might be useful in learning more about autism.

Source: Nakamura T, Arima-Yoshida F, Sakaue F, et al. PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking. Nature Communications. 2016.