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 5

Shank2 deficiency in the neocortex and hippocampus recapitulates the mania-like behavior in global Δe24–/– mice.

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Shank2 deficiency in the neocortex and hippocampus recapitulates the ma...
(A and B) Motor performance on the rotarod was abnormal (A) in Δe24Pcp2–/– mice (RMANOVA: *P < 0.05, +/+ vs. Pcp2–/– mice; n = 6 for Pcp2–/– and n = 15 for +/+ mice), whereas (B) Δe24Emx1–/– mice were unaffected on this task (n = 12–13 mice/genotype). (C and D) Locomotor activities in the open field for (C) Δe24Pcp2–/– mice were indistinguishable from e24+/+ controls, whereas locomotion was augmented (D) in Δe24Emx1–/– mice relative to e24+/+ mice (RMANOVA: *P < 0.05, +/+ vs. Emx1–/– mice; n = 14–15 for Pcp2–/– and +/+ mice and n = 7–9 for Emx1–/– and +/+ mice). (E) Locomotor activities in the open field for Δe24CKII–/– mice were not different from their e24+/+ controls (n = 8–12 mice/genotype). (F) In the Morris water maze, acquisition of the task was prolonged in Δe24Emx1–/– mice relative to e24+/+ controls (RMANOVA: *P < 0.05, +/+ vs. Emx1–/– mice; n = 11–13 mice/genotype). (G) In the sociability test, the social affiliation preference score of Δe24Emx1–/– was borderline higher (RMANOVA: P = 0.067) in male and significantly higher in female (RMANOVA: *P < 0.05) Δe24Emx1–/– mice. NSNS, nonsocial-nonsocial pairing; NSS1, nonsocial-novel social 1 pairing (n = 8–11 mice/genotype/sex). (H) Acute administration of VPA attenuated the hyperactivity in Δe24Emx1–/– mice compared with that of vehicle-treated (VEH-treated) mutants (2-way ANOVA: *P < 0.05, +/+ vs. –/–; &P < 0.05, +/+ vs. –/– VPA-treated; ^P < 0.05, VPA-treated vs. vehicle-treated –/–), whereas locomotion in e24+/+ mice was unaffected by this treatment (n = 11–15 mice/genotype/treatment).