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A possible treatment for autism-like symptoms

The anti-anxiety drug clonazepam reduces autistic behaviors in mice with Jacobsen syndrome. About half of children born with Jacobsen, a rare inherited disorder, experience social and behavioral issues found in autism spectrum disorders.

Researchers at the University of California San Diego School of Medicine along with collaborators from the Laboratory of Molecular and Genetic Information at the Institute of Molecular and Cellular Biosciences, The University of Tokyo, have developed a mouse model of Jacobsen syndrome that also exhibits autism-like social behaviors.

Using this mouse model, they have begun to unravel the molecular mechanisms connecting this genetic defect to its affect on brain function. Published in Nature Communications, the study also demonstrates how the anti-anxiety drug clonazepam reduces autistic features in Jacobsen syndrome mice.

"While this study focused on mice with a specific type of genetic mutation that led to autism-like symptoms, these findings could lead to a better understanding of the molecular mechanisms underlying other autism spectrum disorders, and provide a guide for the development of new potential therapies," hopes study co-author Paul Grossfeld MD, Clinical Professor of Pediatrics at the University of California San Diego School of Medicine, and Pediatric Cardiologist at Rady Children's Hospital-San Diego.

Jacobsen syndrome is a rare genetic disorder in which a child is born missing a portion of one copy of chromosome 11. This gene loss leads to multiple clinical challenges, such as congenital heart disease, intellectual disability, developmental and behavioral problems, slow growth and failure to thrive.

Previous research by Grossfeld and colleagues pointed to PX-RICS as the possible missing chromosome 11 leading to Jacobsen syndrome autism. To investigate further, Grossfeld collaborated with University of Tokyo researchers who study PX-RICS for its role in development, but were unaware of its link to autism in humans. In the joint study, Japanese researchers confirmed PX-RICS as the gene most likely responsible for Jacobsen autism-like symptoms.

Compared to normal mice, mice lacking PX-RICS spent less time on social activities (e.g., nose-to-nose sniffing and huddling) and are more apathetic or avoid being approached by a mouse seeking interaction. PX-RICS-deficient mice also spend more than twice as much time on repetitive behaviors such as self-grooming and digging, than normal mice. PX-RICS deficient mice also closely adhere to habit, being less able to adapt to new situations.

Grossfeld's colleagues in Tokyo explored the molecular connections around the lack of PX-RICS— finding mice without the PX-RICS gene are also deficient in GABAAR, a protein crucial in normal neuron function.

Researchers now saw a possible means to influence the PX-RICS - GABAAR deficiency. They introduced clonazepam. Clonazepam is a commonly used anti-anxiety drug which boosts GABAAR. But would it affect autism-like symptoms in Jacobsen syndrome mice?

Treated with low (non-sedating) doses of clonazepam, PX-RICS deficient mice began behaving almost normally in social tests. They showed improvements in learning performance and were better able to deviate from fixed habits.

"We now hope in the future to carry out a small pilot clinical trial on people with Jacobsen syndrome and autism to determine if clonazepam might help improve their autistic features," Grossfeld adds.

Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.

Study co-authors include Tsutomu Nakamura, Fumiko Arima-Yoshida, Fumika Sakaue, Yukiko Nasu-Nishimura, Yasuko Takeda, Ken Matsuura, Toshiya Manabe, Tetsu Akiyama, University of Tokyo; Natacha Ackshoomoff, UC San Diego; and Sarah Mattson, San Diego State University.

This research was funded, in part, by Grants-in-Aid for Scientific Research, Takeda Science Foundation, Uehara Memorial Foundation, Global COE Program and Strategic Research Program for Brain Sciences, MEXT, Japan.

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Mar 23, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Model for how deletion of the RICS gene causes autism in Jacobsen syndrome. Treatment of RICS-deficient
mice with a commonly used anti-anxiety drug eliminates the autistic features in these mice.
Image Credit: UCSD School of Medicine




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