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Decrease of GSK-3? Activity in the Anterior Cingulate Cortex of Shank3b ^-/- Mice Contributes to Synaptic and Social Deficiency.

ABSTRACT: Social deficiency is one of the core syndromes of autism spectrum disorders (ASD), for which the underlying developmental mechanism still remains elusive. Anterior cingulate cortex (ACC) plays a key role in integrating social information and regulating social behavior. Recent studies have indicated that synaptic dysfunction in ACC is essential for ASD social defects. In the present study, we investigated the development of synapses and the roles of glycogen synthase kinase 3? (GSK-3?), which mediates multiple synaptic signaling pathways in ACC by using Shank3b ^-/- mice (a widely used ASD mouse model). Our data revealed that Shank3b mutation abolished the social induced c-Fos expression in ACC. From 4 weeks post-birth, neurons in Shank3b ^-/- ACC exhibited an obvious decrease in spine density and stubby spines. The length and thickness of post-synaptic density (PSD), the expression of vesicular glutamate transporter 2 (vGlut2) and glutamate receptor 2 (GluR2), and the frequency of miniature excitatory post-synaptic currents (mEPSCs) were significantly reduced in Shank3b ^-/-ACC. Interestingly, the levels of phosphorylated GSK-3? (Ser9), which inhibits the activity of GSK-3?, decreased along the same time course as the levels of GluR2 increased in ACC during development. Shank3b mutation leads to a dramatic increase of pGSK-3? (Ser9), and decrease of pPSD95 (a substrate of GSK-3?) and GluR2. Local delivery of AAV expressing constitutively active GSK-3? restored the expression of GluR2, increased the spine density and the number of mature spines. More importantly, active GSK-3? significantly promoted the social activity of Shank3b ^-/- mice. These data, in together, indicate that decrease of GSK-3? activity in ACC may contribute to the synaptic and social defects of Shank3b ^-/- mice. Enhancing GSK-3? activity may be utilized to treat ASD in the future.

SUBMITTER: Wang M

PROVIDER: S-EPMC6843030 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Decrease of GSK-3β Activity in the Anterior Cingulate Cortex of <i>Shank3b</i> <sup>-/-</sup> Mice Contributes to Synaptic and Social Deficiency.

Wang Mengmeng M Liu Xinyan X Hou Yilin Y Zhang Haifeng H Kang Junjun J Wang Fei F Zhao Youyi Y Chen Jing J Liu Xufeng X Wang Yazhou Y Wu Shengxi S

Frontiers in cellular neuroscience 20191023

Social deficiency is one of the core syndromes of autism spectrum disorders (ASD), for which the underlying developmental mechanism still remains elusive. Anterior cingulate cortex (ACC) plays a key role in integrating social information and regulating social behavior. Recent studies have indicated that synaptic dysfunction in ACC is essential for ASD social defects. In the present study, we investigated the development of synapses and the roles of glycogen synthase kinase 3β (GSK-3β), which med ...[more]

PMID: 31749684

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Project description:Despite its devastating clinical and societal impact, approaches to treat delirium in older adults remain elusive, making it important to identify factors that may confer resilience to this syndrome. Here, we investigated a cohort of 93 cognitively normal older patients undergoing elective surgery recruited as part of the Successful Aging after Elective Surgery study. Each participant was classified either as a SuperAger (n = 19) or typically aging older adult (n = 74) based on neuropsychological criteria, where the former was defined as those older adults whose memory function rivals that of young adults. We compared these subgroups to examine the role of preoperative memory function in the incidence and severity of postoperative delirium. We additionally investigated the association between indices of postoperative delirium symptoms and cortical thickness in functional networks implicated in SuperAging based on structural magnetic resonance imaging data that were collected preoperatively. We found that SuperAging confers the real-world benefit of resilience to delirium, as shown by lower (i.e. zero) incidence of postoperative delirium and decreased severity scores compared with typical older adults. Furthermore, greater baseline cortical thickness of the anterior mid-cingulate cortex-a key node of the brain's salience network that is also consistently implicated in SuperAging-predicted lower postoperative delirium severity scores in all patients. Taken together, these findings suggest that baseline memory function in older adults may be a useful predictor of postoperative delirium risk and severity and that superior memory function may contribute to resilience to delirium. In particular, the integrity of the anterior mid-cingulate cortex may be a potential biomarker of resilience to delirium, pointing to this region as a potential target for preventive or therapeutic interventions designed to mitigate the risk or consequences of developing this prevalent clinical syndrome.

Dataset Information

Decrease of GSK-3? Activity in the Anterior Cingulate Cortex of Shank3b ^-/- Mice Contributes to Synaptic and Social Deficiency.

Publications

Decrease of GSK-3β Activity in the Anterior Cingulate Cortex of <i>Shank3b</i> <sup>-/-</sup> Mice Contributes to Synaptic and Social Deficiency.

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Dataset Information

Decrease of GSK-3? Activity in the Anterior Cingulate Cortex of Shank3b -/- Mice Contributes to Synaptic and Social Deficiency.

Publications

Decrease of GSK-3β Activity in the Anterior Cingulate Cortex of <i>Shank3b</i> <sup>-/-</sup> Mice Contributes to Synaptic and Social Deficiency.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Decrease of GSK-3? Activity in the Anterior Cingulate Cortex of Shank3b ^-/- Mice Contributes to Synaptic and Social Deficiency.