title: PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking.
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.
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Arima-Yoshida
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Sakaue
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nasu-Nishimura
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Natacha
authors.initials: N
authors.lastname: Akshoomoff
authors.affiliation: Department of Psychology, San Diego State University, San Diego, California 92120, USA.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Mattson
authors.affiliation: Department of Pediatrics, School of Medicine, University of California, San Diego, San Diego, California 92123, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Grossfeld
authors.affiliation: Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Manabe
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D002998:Clonazepam / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018757:GABA Modulators / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006120:Grooming; D054868:Jacobsen Distal 11q Deletion Syndrome / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D055696:Olfactory Perception / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000235:genetics*; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D014828:Vocalization, Animal / Q000187:drug effects / Q000502:physiology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018757:GABA Modulators; C477752:GC-GAP protein, mouse; D020690:GTPase-Activating Proteins; D011963:Receptors, GABA-A; D002998:Clonazepam; D007608:Kainic Acid