Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers
Andrea L. Pappas, … , William C. Wetsel, Yong-hui Jiang
Andrea L. Pappas, … , William C. Wetsel, Yong-hui Jiang
Published October 19, 2017
Citation Information: JCI Insight. 2017;2(20):e92052. https://doi.org/10.1172/jci.insight.92052.
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Research Article Genetics Neuroscience

Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers

Abstract

Genetic defects in the synaptic scaffolding protein gene, SHANK2, are linked to a variety of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, intellectual disability, and bipolar disorder, but the molecular mechanisms underlying the pleotropic effects of SHANK2 mutations are poorly understood. We generated and characterized a line of Shank2 mutant mice by deleting exon 24 (Δe24). Shank2Δe24–/– mice engage in significantly increased locomotor activity, display abnormal reward-seeking behavior, are anhedonic, have perturbations in circadian rhythms, and show deficits in social and cognitive behaviors. While these phenotypes recapitulate the pleotropic behaviors associated with human SHANK2-related disorders, major behavioral features in these mice are reminiscent of bipolar disorder. For instance, their hyperactivity was augmented with amphetamine but was normalized with the mood stabilizers lithium and valproate. Shank2 deficiency limited to the forebrain recapitulated the bipolar mania phenotype. The composition and functions of NMDA and AMPA receptors were altered at Shank2-deficient synapses, hinting toward the mechanism underlying these behavioral abnormalities. Human genetic findings support construct validity, and the behavioral features in Shank2 Δe24 mice support face and predictive validities of this model for bipolar mania. Further genetic studies to understand the contribution of SHANK2 deficiencies in bipolar disorder are warranted.

Authors

Andrea L. Pappas, Alexandra L. Bey, Xiaoming Wang, Mark Rossi, Yong Ho Kim, Haidun Yan, Fiona Porkka, Lara J. Duffney, Samantha M. Phillips, Xinyu Cao, Jin-dong Ding, Ramona M. Rodriguiz, Henry H. Yin, Richard J. Weinberg, Ru-Rong Ji, William C. Wetsel, Yong-hui Jiang

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Figure 1

Generation of Shank2Δe24 mutant mice and mania-like behaviors in these mutants.

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Generation of Shank2Δe24 mutant mice and mania-like behaviors in these m...
(A) Generation strategy for e24 floxed (e24flox) mice and deletion of exon 24 (Δe24) (arrows show genotyping primers X, Y, and Z listed in Supplemental Table 2). The construct shows the loxP (green), FRT (blue), and the Neo cassette (yellow) sites. (B) Genotyping of Δe24+/flox mice by Southern blot using a 5′ flanking probe. WT, wild type. MT, mutant. (C) Genotyping e24+/+, Δe24+/–, and Δe24–/– mice by PCR using primers X, Y, and Z as diagramed. (D) Absence of SHANK2 protein by western blotting in hippocampus, neocortex, and striatum in e24+/+ and Δe24–/– mice. (E) Augmented open-field locomotor activity in Δe24–/– mice compared with Δe24+/– and e24+/+ animals depicted in 5-minute segments (left) or as cumulative distance traveled (0–60 minutes) (right). The data are presented as mean ± SEM. *P < 0.05, +/+ vs. –/–; #P < 0.05, +/– vs. –/–; n = 8–9 mice/genotype (see Supplemental Table 1 for details of the animal cohorts used for the behavioral analysis and Supplemental Table 5 for details of the statistical analyses for all behavioral tests). (F) Profiles of locomotion in first and last 15 minutes during the 60-minute test in open field show that Δe24–/– mice were hyperactive and failed to exhibit habituation during exposure to the open field relative to e24+/+ control. (G) Locomotor activity in the open field in 10-minute segments (left) and as cumulative distance traveled (right) in Δe24–/– mice were higher than that for e24+/+ and Δe24+/– mice during both the light and dark phases over a 48-hour period (RMANOVA: *P < 0.05, +/+ vs. –/–; #P < 0.05, +/– vs. –/–; n = 8–9 mice/genotype). (H) Latency to fall from the rotarod was decreased in Δe24–/– mice compared with e24+/+ mice (RMANOVA: *P < 0.05, +/+ vs. –/–; n = 20–21 mice). (I) Acute treatment with amphetamine (AMPH) augmented the hyperactivity in Δe24–/– mice relative to untreated animals. The percentage increase in the cumulative distance traveled in Δe24–/– mice relative to baseline (2-way ANOVA: &P < 0.05, AMPH treated vs. vehicle; *P < 0.05, AMPH treated +/+ vs. –/–; n = 7–9 mice/genotype).