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
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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 6

Altered PSD ultrastructure, NMDAR- and AMPAR-mediated currents, and the expression of NMDAR subunits in Δe24–/– hippocampus.

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Altered PSD ultrastructure, NMDAR- and AMPAR-mediated currents, and the ...
(A) PSD structure in synapses of hippocampus CA1, striatum, and cerebellum of e24+/+ and Δe24–/– mice by electron microscopy. Note the slight but statistically significant reduction of dark part of PSD in hippocampal CA1 synapses but not striatal and cerebellar synapses in Δe24–/– mice (see Table 1). Scale bar: 200 mm. (B and C) The NMDA currents in hippocampal CA1 neurons of Δe24–/– mice were reduced in response to the bath application of NMDA than those from e24+/+ mice. Traces and image of a cell being patched for recording in B (original magnification, ×40) and quantification of NMDA-induced currents for e24+/+ and Δe24–/– mice in B (unpaired 2-tailed t test, *P < 0.05, +/+ vs. –/– mice; n = 14–16 cells /genotype). (D) Representative traces of evoked NMDAR eEPSCs (at +40 mV) and AMPAR EPSCs (at –70 mV) from whole cells recorded in hippocampal CA1 neurons from Δe24+/+ (black) and Δe24–/– (red) mice. Both of NMDA and AMPA currents were elicited by a 0.25-ms duration and 300-μA stimulation intensity. (E) Reduced NMDAR-mediated eEPSCs in hippocampal CA1 neurons of Δe24–/– mice (+/+ vs. –/–; P = 0.001, unpaired 2-tailed t test). (F) Increased AMPAR-mediated EPSCs in hippocampal CA1 neurons of Δe24–/– mice (+/+ vs. –/–; P = 0.006, unpaired 2-tailed t test). (G) Reduced NMDA/AMPA ratio in neurons of Δe24–/– mice (+/+ vs. –/–; P = 0.0009, unpaired t test) (n = 19 neurons from 4 Δe24+/+ mice and n = 15 neurons from 3 Δe24–/– animals; error bars show SEM; unpaired 2-tailed t test, *P < 0.01). (H) NR1 protein was reduced in PSD fractions of Δe24–/– hippocampi compared with Δe24+/+ hippocampi. (I and J) NR2A and NR2B subunit proteins were increased in PSD fractions of Δe24–/– hippocampi compared with Δe24+/+ hippocampi. (K and L) NR2C and NR2D subunit proteins were not significantly altered in PSD fractions of Δe24–/– hippocampi compared with Δe24+/+ hippocampi (n = 3–6 mice/genotype, unpaired 2-tailed t test, *P < 0.01 +/+ vs. –/–). (See complete unedited blots in the supplemental material.)