About half of children with Jacobsen syndrome—a rare genetic disorder caused by deletions on chromosome 11—show social and behavioral problems consistent with autism spectrum disorder (ASD). Researchers at the University of California, San Diego School of Medicine, together with collaborators in Japan, created a mouse model that reproduces these autism-like features and used it to identify the molecular link between the genetic deletion and altered brain function.
The study, published March 16, 2016 in Nature Communications, also reports that the anti-anxiety medication clonazepam reduces autism-like features in the Jacobsen syndrome mouse model, supporting a potential therapeutic approach targeting inhibitory signaling.
Mouse model identifies PX-RICS as a key gene
Jacobsen syndrome results from a terminal deletion on the long arm of chromosome 11 and causes a spectrum of medical and developmental problems including congenital heart defects, intellectual disability, growth delay and behavioral disturbances. Prior clinical and genetic work suggested that loss of the gene PX-RICS, located in the commonly deleted region, could underlie autistic features in some patients.
To test that hypothesis, researchers collaborated with a team in Tokyo already studying PX-RICS in brain development. They generated mice lacking PX-RICS and evaluated them using established behavioral assays that measure the three core domains of ASD: social interaction, repetitive behaviors, and cognitive flexibility.
Compared with control mice, PX-RICS-deficient animals showed clear autism-like behaviors: reduced social interactions such as nose-to-nose sniffing and huddling, social avoidance when an unfamiliar mouse approached, and a marked increase in repetitive actions (more than double the time spent self-grooming and digging). These mice also displayed increased rigidity in habits and had difficulty adapting their behavior in new situations, consistent with impaired cognitive flexibility.
Molecular mechanism: impaired GABAA receptor trafficking
To connect the behavioral phenotype to cellular mechanisms, the team examined synaptic proteins and signaling pathways. PX-RICS-deficient neurons had lower surface levels of the γ-aminobutyric acid type A receptor (GABAA receptor, or GABAAR), a key mediator of inhibitory neurotransmission in the brain. Electrophysiological measures showed impaired GABAAR-mediated synaptic transmission in the absence of PX-RICS.
Biochemical studies revealed that PX-RICS forms an adaptor complex with GABARAP and 14-3-3ζ/θ proteins. This complex appears to link GABAARs to microtubule-based motor machinery (dynein/dynactin), facilitating receptor trafficking to the neuronal surface. Loss of PX-RICS disrupts this trafficking, reducing inhibitory signaling and producing neural circuit imbalances that likely contribute to ASD-like behaviors.
Clonazepam rescues behavioral deficits in mice
Given the reduced GABAAR expression and impaired inhibitory transmission in PX-RICS-deficient mice, researchers tested clonazepam, a clinically used benzodiazepine that enhances GABAAR function. At low, non-sedating doses, clonazepam-treated PX-RICS-deficient mice showed substantial behavioral improvements: social interactions increased toward normal levels, learning and performance improved, and animals became better able to break established habits and adapt to new tasks.
These findings show that enhancing inhibitory synaptic transmission can ameliorate ASD-like features in this genetic model and support the idea that PX-RICS deletion contributes causally to autism-related symptoms in Jacobsen syndrome through defective GABAAR trafficking.
Implications and next steps
While the study focused on a particular genetic lesion linked to Jacobsen syndrome, the molecular pathway it highlights—PX-RICS-dependent trafficking of GABAARs—may be relevant to other forms of ASD in which inhibitory signaling is disrupted. The mouse model offers a tractable platform for testing interventions that restore inhibitory balance in affected circuits.
Encouraged by the preclinical results, the research team expressed interest in pursuing a small pilot clinical trial to evaluate whether drugs that enhance GABAAR function, such as low-dose clonazepam, might improve autistic features in people with Jacobsen syndrome who also have ASD.
Study authors include Tsutomu Nakamura, Fumiko Arima-Yoshida, Fumika Sakaue, Yukiko Nasu-Nishimura, Yasuko Takeda, Ken Matsuura, Toshiya Manabe and Tetsu Akiyama (University of Tokyo); Natacha Akshoomoff (UC San Diego); Sarah Mattson (San Diego State University); and Paul D. Grossfeld (UC San Diego School of Medicine and Rady Children’s Hospital-San Diego).
Funding: The research received support from Grants-in-Aid for Scientific Research, the Takeda Science Foundation, Uehara Memorial Foundation, the Global COE Program, and the Strategic Research Program for Brain Sciences, MEXT, Japan.
Abstract (summary)
Jacobsen syndrome is caused by deletion of part of chromosome 11 and a subset of patients develop autism spectrum disorder. PX-RICS is located in the chromosomal region commonly deleted in patients with autistic-like behavior. PX-RICS-deficient mice exhibit ASD-like social behaviors and related comorbidities. Neurons lacking PX-RICS show reduced surface GABAA receptor levels and impaired GABAA receptor-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that connects GABAA receptors to dynein/dynactin, promoting GABAA receptor surface expression. Enhancing inhibitory synaptic transmission with a GABAA receptor agonist ameliorates ASD-like behaviors in PX-RICS-deficient mice, supporting a causal link between PX-RICS deletion and ASD-like behavior in Jacobsen syndrome.