TY - JOUR
T1 - Mice lacking GRIP1/2 show increased social interactions and enhanced phosphorylation at GluA2-S880
AU - Han, Mei
AU - Mejias, Rebeca
AU - Chiu, Shu Ling
AU - Rose, Rebecca
AU - Adamczyk, Abby
AU - Huganir, Richard
AU - Wang, Tao
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - 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.
AB - 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.
KW - Autism
KW - Frontal cortex
KW - GABAβ3
KW - GRIPs
KW - GluA2-S880
KW - Social interaction
UR - http://www.scopus.com/inward/record.url?scp=85008939503&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85008939503&partnerID=8YFLogxK
U2 - 10.1016/j.bbr.2016.12.042
DO - 10.1016/j.bbr.2016.12.042
M3 - Article
C2 - 28063882
AN - SCOPUS:85008939503
SN - 0166-4328
VL - 321
SP - 176
EP - 184
JO - Behavioural Brain Research
JF - Behavioural Brain Research
ER -