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

Publication ,  Journal Article
Pappas, AL; Bey, AL; Wang, X; Rossi, M; Kim, YH; Yan, H; Porkka, F; Duffney, LJ; Phillips, SM; Cao, X; Ding, J-D; Rodriguiz, RM; Yin, HH ...
Published in: JCI Insight
October 19, 2017

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.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

October 19, 2017

Volume

2

Issue

20

Location

United States

Related Subject Headings

  • Synapses
  • Social Behavior Disorders
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, AMPA
  • Prosencephalon
  • Phenotype
  • Nerve Tissue Proteins
  • N-Methylaspartate
  • Motor Activity
  • Mice, Knockout
 

Citation

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Pappas, A. L., Bey, A. L., Wang, X., Rossi, M., Kim, Y. H., Yan, H., … Jiang, Y.-H. (2017). Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI Insight, 2(20). https://doi.org/10.1172/jci.insight.92052
Pappas, Andrea L., Alexandra L. Bey, Xiaoming Wang, Mark Rossi, Yong Ho Kim, Haidun Yan, Fiona Porkka, et al. “Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers.JCI Insight 2, no. 20 (October 19, 2017). https://doi.org/10.1172/jci.insight.92052.
Pappas AL, Bey AL, Wang X, Rossi M, Kim YH, Yan H, et al. Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI Insight. 2017 Oct 19;2(20).
Pappas, Andrea L., et al. “Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers.JCI Insight, vol. 2, no. 20, Oct. 2017. Pubmed, doi:10.1172/jci.insight.92052.
Pappas AL, Bey AL, Wang X, Rossi M, Kim YH, Yan H, Porkka F, Duffney LJ, Phillips SM, Cao X, Ding J-D, Rodriguiz RM, Yin HH, Weinberg RJ, Ji R-R, Wetsel WC, Jiang Y-H. Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI Insight. 2017 Oct 19;2(20).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

October 19, 2017

Volume

2

Issue

20

Location

United States

Related Subject Headings

  • Synapses
  • Social Behavior Disorders
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, AMPA
  • Prosencephalon
  • Phenotype
  • Nerve Tissue Proteins
  • N-Methylaspartate
  • Motor Activity
  • Mice, Knockout