PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking

Tsutomu Nakamura (), Fumiko Arima-Yoshida, Fumika Sakaue, Yukiko Nasu-Nishimura, Yasuko Takeda, Ken Matsuura, Natacha Akshoomoff, Sarah N. Mattson, Paul D. Grossfeld, Toshiya Manabe and Tetsu Akiyama
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Tsutomu Nakamura: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Fumiko Arima-Yoshida: Institute of Medical Science, The University of Tokyo
Fumika Sakaue: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Yukiko Nasu-Nishimura: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Yasuko Takeda: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Ken Matsuura: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo
Natacha Akshoomoff: School of Medicine, University of California, San Diego
Sarah N. Mattson: San Diego State University
Paul D. Grossfeld: School of Medicine, University of California, San Diego
Toshiya Manabe: Institute of Medical Science, The University of Tokyo
Tetsu Akiyama: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms10861

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