Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers
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
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
View: Text | PDF
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

×

Figure 2

Anhedonia, lever pressing, circadian rhythms, and responses to lithium and VPA in Shank2Δe24 mice.

Options: View larger image (or click on image) Download as PowerPoint
Anhedonia, lever pressing, circadian rhythms, and responses to lithium a...
(A) Δe24–/– and e24+/+ mice consume similar volumes of liquid, but Δe24–/– mice show a significantly reduced preference for sucrose (2-tailed t test: *P < 0.01, +/+ vs. –/–; n = 26–28 mice/genotype). (B) Under the continuous reinforcement schedule of 1:1, numbers of total lever presses were similar for e24+/+ and Δe24–/– mice. (C) Δe24–/– mice had significantly more food cup entries than e24+/+ controls. (D) Under the RR20 schedule of reinforcement, Δe24–/– mice pressed at a higher rate than e24+/+ controls. (E) Press rates between genotypes were similar during extinction (unrewarded) but were significantly different during reward and reinstatement phases. (F) Breakpoints were similar between e24+/+ and Δe24–/– mice during a progressive ratio test (2-tailed t test: *P < 0.05, +/+ vs. –/–; n = 16–17 mice/genotype). (G and H) Δe24–/– mice have abnormal circadian rhythms. Representative actograms of motor activity for e24+/+ (F) and Δe24–/– (G) mice. Mice were first entrained to a 12:12-hour-light/dark cycle before being placed into continuous darkness for a free-run period. After 32–34 days, mice were exposed to a 6-hour light pulse (red arrow). e24+/+ mice entrained, whereas Δe24–/– mice did not entrain to the pulse. Both genotypes reentrained to the 12:12-hour-light/dark cycle following the free-run period. (I) Lithium reversed abnormal circadian rhythm in Δe24–/– mice and enabled mutants to respond to the 6-hour light pulse (n = 8–10 mice/genotype/treatment). (J–L) Phase shift (J), but not Tau (K) or phase angle (L), was abnormal in Δe24–/– mice. Lithium restored this parameter (I) to levels of e24+/+ mice (RMANOVA: *P < 0.05, +/+ vs. –/–; #P < 0.05+/+ vs. +/+ lithium treated within genotype; ^P < 0.05, –/– vs. –/– lithium treated within genotype; n = 8–10 mice/genotype/treatment for F–K). (M) Acute administration of VPA reduced locomotor activity of Δe24–/– mice in open field to that of e24+/+ vehicle controls (2-way ANOVA: *P < 0.05, +/+ VEH vs. –/– VEH treated; ^P < 0.05, –/– VEH vs. –/– VPA treated; n = 11 mice/genotype/treatment). (N) Lithium partially reduced hyperlocomotion in Δe24–/– mice to that of e24+/+ controls (2-way ANOVA: *P < 0.05, +/+ VEH vs. –/– VEH-treated; #P < 0.05, –/– VEH vs. –/– lithium-treated; &P < 0.05, +/+ lithium vs. –/– lithium treated. P = 0.027 for treatment × genotype interaction; n = 5–12 mice/genotype/treatment).