Deletion of Glycogen Synthase Kinase-3β in D2 Receptor–Positive Neurons Ameliorates Cognitive Impairment via NMDA Receptor–Dependent Synaptic Plasticity

Li, Yan Chun; Panikker, Priyalakshmi; Xing, Bo; Yang, Sha; Alexandropoulos, Cassandra; McEachern, Erin; Akumuo, Rita; Zhao, Elise E.; Gulchina, Yelena; Pletnikov, Mikhail V.; Urs, Nikhil M.; Caron, Marc G.; Elefant, Felice; Gao, Wen-Jun

doi:10.1016/j.biopsych.2019.10.025

Cited by 17 publications

(6 citation statements)

References 68 publications

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“…GSK-3β is postulated to play an important role in cognitive function and psychiatric behaviors. 43 , 49 , 50 , 51 To characterize the effects of GSK-3β K15-acetylation on the cognitive ability of mice, we stereotaxically injected adeno-associated virus (AAV) vectors carrying GSK-3β WT (AAV-GSK-3β WT ), GSK-3β K15Q (AAV-GSK-3β K15Q ), or the empty vector control with non-fusion eGFP into 2-month-old C57 mice hippocampal CA1 subset. After 1 month, GSK-3β overexpression in CA1 was confirmed by GFP imaging ( Figure 4 a) and Western blotting ( Figure 4 b).…”

Section: Resultsmentioning

confidence: 99%

Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration

Zhou

et al. 2022

eBioMedicine

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Section: Resultsmentioning

confidence: 99%

Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration

Zhou

et al. 2022

eBioMedicine

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“…In another study on cortical neurons lacking GSK3β targeted through crosses of our floxed mice with Drd2-cre, there were no changes in AMPAR-mediated spontaneous and miniature events (Li et al, 2020). Instead, NMDAR-mediated function was enhanced, a finding that was further substantiated using direct injections of viral Syn-cre into floxed Gsk3b mice.…”

Section: Does Gsk3β Play Any Critical Role In Ca1 Long-term Potentiat...mentioning

confidence: 57%

Specific Role for GSK3α in Limiting Long-Term Potentiation in CA1 Pyramidal Neurons of Adult Mouse Hippocampus

Amini

Miyata

Liu

et al. 2022

Front. Mol. Neurosci.

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Glycogen synthase kinase-3 (GSK3) mediates phosphorylation of several hundred proteins, and its aberrant activity is associated with an array of prevalent disorders. The two paralogs, GSK3α and GSK3β, are expressed ubiquitously and fulfill common as well as unique tasks throughout the body. In the CNS, it is established that GSK3 is involved in synaptic plasticity. However, the relative roles of GSK3 paralogs in synaptic plasticity remains controversial. Here, we used hippocampal slices obtained from adult mice to determine the role of each paralog in CA3−CA1 long-term potentiation (LTP) of synaptic transmission, a form of plasticity critically required in learning and memory. Conditional Camk2a Cre-driven neuronal deletion of the Gsk3a gene, but not Gsk3b, resulted in enhanced LTP. There were no changes in basal synaptic function in either of the paralog-specific knockouts, including several measures of presynaptic function. Therefore, GSK3α has a specific role in serving to limit LTP in adult CA1, a postsynaptic function that is not compensated by GSK3β.

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“…The GSK3β is a kinase that plays a role in the etiology of AD, and it performs biological functions after being dephosphorylated (p-GSK3β) by upstream proteins like PP2A ( Elgendy et al, 2019 ). Also, GSK3β may be explored as a potential therapeutic target for AD through a mechanism that improves dopamine-dependent memory behaviors via modulating D2 receptor (D2R)-mediated signaling ( Li et al, 2020 ), supporting the association to dopaminergic synapse pathway. Furthermore, the interaction between GSK3β and PP2A have been established, that PP2A, the main phosphatase could regulate GSK3β activity by removing phosphorylation at serine 9 ( Elgendy et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Chinese Herbal Extracts Exert Neuroprotective Effect in Alzheimer’s Disease Mouse Through the Dopaminergic Synapse/Apoptosis Signaling Pathway

Huang

Zhang

et al. 2022

Front. Pharmacol.

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Background: Alzheimer’s disease (AD) as an age-related, irreversible neurodegenerative disease, characterized by cognitive dysfunction, has become progressively serious with a global rise in life expectancy. As the failure of drug elaboration, considerable research effort has been devoted to developing therapeutic strategies for treating AD. TCM is gaining attention as a potential treatment for AD. Gastrodia elata Blume, Polygala tenuifolia Willd., Cistanche deserticola Ma, Rehmannia lutinosa (Gaertn.)DC., Acorus gramineus Aiton, and Curcuma longa L. (GPCRAC) are all well-known Chinese herbs with neuroprotective benefits and are widely used in traditional Chinese decoction for AD therapy. However, the efficacy and further mechanisms of GPCRAC extracts in AD experimental models are still unclear. The purpose of this study was to investigate the synergistic protective efficacy of GPCRAC extracts (composed of extracts from these six Chinese medicines), and the protein targets mediated by GPCRAC extracts in treating AD.Methods: Scopolamine-induced cognitive impairment mouse model was established to determine the neuroprotective effects of GPCRAC extracts in vivo, as shown by behavioral tests and cerebral cholinergic function assays. To identify the potential molecular mechanism of GPCRAC extracts against AD, label-free quantitative proteomics coupled with tandem mass spectrometry (LC-MS/MS) were performed. The integrated bioinformatics analysis was applied to screen the core differentially expressed proteins in vital canonical pathways. Critical altered proteins were validated by qPCR and Western blotting.Results: Administration of GPCRAC extracts significantly recovered scopolamine-induced cognitive impairment, as evidenced by the improved learning and memory ability, increased Ach content and ChAT activity, as well as decreased AchE activity in the hippocampus of mice. In total, 390 proteins with fold-change>1.2 or <0.83 and p < 0.05 were identified as significant differentially expressed proteins, of which 110 were significantly up-regulated and 25 were significantly down-regulated between control and model group. By mapping the significantly regulated proteins, we identified five hub proteins: PPP2CA, Gsk3β, PP3CC, PRKACA, and BCL-2 that were associated with dopaminergic synapse and apoptosis signaling pathway, respectively. Western blotting and QPCR demonstrate that the expression levels of these core proteins could be significantly improved by the administration of GPCRAC extracts. These pathways and some of the identified proteins are implicated in AD pathogenesis.Conclusion: Administration of GPCRAC extracts was effective on alleviating scopolamine-induced cognitive impairment, which might be through modulation of dopaminergic synapse and apoptosis signaling pathway. Consequently, our quantitative proteome data obtained from scopolamine-treated model mice successfully characterized AD-related biological alterations and proposed novel protein biomarkers for AD.

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Deletion of Glycogen Synthase Kinase-3β in D2 Receptor–Positive Neurons Ameliorates Cognitive Impairment via NMDA Receptor–Dependent Synaptic Plasticity

Cited by 17 publications

References 68 publications

Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration

Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration

Specific Role for GSK3α in Limiting Long-Term Potentiation in CA1 Pyramidal Neurons of Adult Mouse Hippocampus

Chinese Herbal Extracts Exert Neuroprotective Effect in Alzheimer’s Disease Mouse Through the Dopaminergic Synapse/Apoptosis Signaling Pathway

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