title: Mice lacking GRIP1/2 show increased social interactions and enhanced phosphorylation at GluA2-S880.
abstract: Glutamate receptor interacting proteins 1 and 2 (GRIP1/2) play an important role in regulating synaptic trafficking of AMPA receptor 2/3 (GluA2/3) and synaptic strength. Gain-of-function GRIP1 mutations are implicated in social behavioral deficits in autism. To study mechanisms of Grip1/2-mediated AMPA signaling in the regulation of social behaviors, we performed social behavioral testing on neuron-specific Grip1/2-double knockout (DKO) and wild type (WT) mice that are matched for age, sex, and strain background. We determined the expression profile of key signaling proteins in AMPAR, mGluR, mTOR, and GABA pathways in frontal cortex, striatum, and cerebellum of DKO mice. Compared to WT mice, DKO mice show increased sociability in a modified three-chamber social behavioral test [mean±sem for interaction time in seconds; WT: 44.0±5.0; n=10; DKO: 81.0±9.0; n=9; two factor repeated measures ANOVA: F(1,37)=14.45; p<0.01 and planned t-test; p<0.01] and in a dyadic male-male social interaction test (mean±sem for total time in seconds: sniffing, WT-WT, 18.9±1.1; WT-DKO, 42.5±2.1; t-test: p<0.001; following, WT-WT, 7.7±0.72; WT-DKO,14.4±1.8; t-test: p<0.001). Immunoblot studies identified an increase in phosphorylation at GluA2-Serine 880 (GluA2-pS880) in frontal cortex (mean±sem; WT: 0.69±0.06, n=5; DKO: 0.96±0.06, n=6; t-test; p<0.05) and reduced GABAβ3 expression in striatum (mean±sem; WT: 1.16±0.04, n=4; DKO: 0.95±0.06, n=4; t-test; p<0.05) in DKO mice. GluA2-S880 phosphorylation is known to regulate GluA2synaptic recycling, AMPA signaling strength and plasticity. GABAβ3 has been implicated in the etiology and pathogenesis in autism. These data support an important role of Grip1/2-mediated AMPA signaling in regulating social behaviors and disturbance of glutamate- and GABA-signaling in specialized brain regions in autism-related social behavioral deficits.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Mejias
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Chiu
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rose
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Abby
authors.initials: A
authors.lastname: Adamczyk
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Huganir
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, MD, 21205, USA. Electronic address: twang9@jhmi.edu.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D000067877:Autism Spectrum Disorder; D002352:Carrier Proteins / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012919:Social Behavior; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C491309:Grip1 protein, mouse; C485567:Grip2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D018079:Receptors, GABA; D018094:Receptors, Metabotropic Glutamate; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Autism; Frontal cortex; GABAβ3; GRIPs; GluA2-S880; Social interaction