GSK-3β deletion in dentate gyrus excitatory neuron impairs synaptic plasticity and memory

Liu, Enjie; Xie, Ao-Ji; Zhou, Qiuzhi; Li, Mengzhu; Zhang, Shujuan; Li, Shihong; Wang, Weijin; Wang, Xiao-Chuan; Wang, Qun; Wang, Jian‐Zhi

doi:10.1038/s41598-017-06173-4

Cited by 37 publications

(25 citation statements)

References 69 publications

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“…Time spent in the central squares, distance in the central squares, numbers of entries, and the total distance traveled were recorded and analyzed by the video tracking system of SMART 3.0 (Panlab Harvard Apparatus, Spain). After each test, the open-field arena was cleaned with 10% bleach and 75% ethanol ( Davalli et al, 2016 ; Fougere et al, 2017 ; Hekmatimoghaddam et al, 2017 ; Liu E. et al, 2017 ; Costa-Ferreira et al, 2019 ; Zhou et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

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Differentially Expressed Genes in the Brain of Aging Mice With Cognitive Alteration and Depression- and Anxiety-Like Behaviors

Cai

et al. 2020

Front. Cell Dev. Biol.

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Despite the great increase in human lifespan with improved medical care, the physiological and pathological changes such as memory and cognitive disorders and associated anxiety and depression are major concern with aging. Molecular mechanisms underlying these changes are little known. The present study examined the differentially expressed genes (DEGs) and the genes with differentially expressed isoforms in three brain regions, anterior cingulate cortex (ACC), amygdala and hippocampus, throughout the lifespan of mice. Compared to 2-month old mice, both 12-and 24-month old mice displayed memory and cognitive impairments in the Morris water maze, Y-maze, and novel object recognition tests and depression-and anxiety-like behaviors in the tail suspension, forced swimming, open field, and elevated plus maze tests. RNA sequencing analysis identified 634 and 1078 DEGs in ACC, 453 and 1015 DEGs in the amygdala and 884 and 1054 DEGs in hippocampus in the 12-and 24-month old mice, respectively. Similarly, many genes with differentially expressed isoforms were also identified in these three brain regions in the 12-and 24-month old mice. Further functional analysis revealed that many DEGs and the genes with differentially expressed isoforms in the ACC and amygdala were mapped to depression-and anxiety-related genes, respectively and that a lot of DEGs and the genes with differentially expressed isoforms in hippocampus were mapped to cognitive dysfunction-related genes from both 12-and 24-month old mice. All of these mapped DEGs and the genes with differentially expressed isoforms were closely related to neuroinflammation. Our findings indicate that these neuroinflammation-related DEGs and the genes with differentially expressed isoforms are likely new targets in the management of memory/cognitive impairment and emotional disorders during the aging.

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Section: Methodsmentioning

confidence: 99%

“…Spatial working memory was tested in the Y-maze spontaneous alternation task ( Liu E. et al, 2017 ). Spontaneous alternation performance was assessed by a gray Plexiglas 3-arm Y-maze (each arm: 30-cm long × 7-cm wide × 15-cm high) under weak light conditions.…”

Section: Methodsmentioning

confidence: 99%

Differentially Expressed Genes in the Brain of Aging Mice With Cognitive Alteration and Depression- and Anxiety-Like Behaviors

Cai

et al. 2020

Front. Cell Dev. Biol.

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“…The “GSK3 hypothesis in AD” suggests that the overactivation of GSK-3 β is closely related to several features of the pathology of AD, including microglia-mediated inflammation, A β production, APP processing, tau phosphorylation, neuronal death, and cognitive deficits [ 52 ]. A recent study revealed that GSK-3 β deletion in the dentate gyrus of mice suppressed hippocampal synaptic transmission and decreased the levels of synapse proteins such as PSD93 and SYN [ 53 ]. Thus, inhibition of GSK-3 β has been found to be beneficial and provide a potential therapeutic target for neurodegenerative diseases [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Magnolol Ameliorates Behavioral Impairments and Neuropathology in a Transgenic Mouse Model of Alzheimer’s Disease

Xian

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

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Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by progressive memory loss. Magnolol (MN), the main active ingredient of Magnolia officinalis, possesses anti-AD effects in several experimental models of AD. In this study, we aimed to explore whether MN could ameliorate the cognitive deficits in TgCRND8 transgenic mice and to elucidate its molecular mechanisms. Male TgCRND8 mice were orally administered with MN (20 and 40 mg/kg) daily for 4 consecutive months, followed by assessing the spatial learning and memory functions using the open-field, radial arm maze, and novel object recognition tests. The results demonstrated that MN (20 and 40 mg/kg) could markedly ameliorate the cognitive deficits in TgCRND8 mice. In addition, MN significantly increased the expression of postsynaptic density protein 93 (PSD93), PSD-95, synapsin-1, synaptotagmin-1, synaptophysin (SYN), and interleukin-10 (IL-10), while markedly reduced the protein levels of tumor necrosis factor alpha (TNF-α), IL-6, IL-1β, Aβ40, and Aβ42, and modulated the amyloid precursor protein (APP) processing and phosphorylation. Immunofluorescence showed that MN significantly suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the hippocampus and cerebral cortex of TgCRND8 mice. Mechanistic studies revealed that MN could significantly increase the ratios of p-GSK-3β (Ser9)/GSK-3β, p-Akt (Ser473)/Akt, and p-NF-κB p65/NF-κB p65. These findings indicate that MN exerted cognitive deficits improving effects via suppressing neuroinflammation, amyloid pathology, and synaptic dysfunction through regulating the PI3K/Akt/GSK-3β and NF-κB pathways, suggesting that MN is a promising naturally occurring polyphenol worthy of further developing into a therapeutic agent for AD treatment.

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“…GSK-3β deletion also suppresses the activity-dependent neural activation and calcium/calmodulin-dependent protein kinase II (CaMKII)/CaMKIV-CREB signaling. These data demonstrate that as overactivation, GSK-3β deletion is also detrimental to the neurons, suggesting that GSK-3β in DG excitatory neurons is essential for maintaining synaptic plasticity and cognitive functions [ 43 ].…”

Section: Role Of Gsk-3β and Pp2a In Tau And Ad Pathologiesmentioning

confidence: 99%

Nature of Tau-Associated Neurodegeneration and the Molecular Mechanisms

Yang

Wang

2018

JAD

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Neurodegeneration is defined as the progressive loss of structure or function of the neurons. As the nature of degenerative cell loss is currently not clear, there is no specific molecular marker to measure neurodegeneration. Therefore, researchers have been using apoptotic markers to measure neurodegeneration. However, neurodegeneration is completely different from apoptosis by morphology and time course. Lacking specific molecular marker has been the major hindrance in research of neurodegenerative disorders. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and tau accumulation forming neurofibrillary tangles is a hallmark pathology in the AD brains, suggesting that tau must play a critical role in AD neurodegeneration. Here we review part of our published papers on tau-related studies, and share our thoughts on the nature of tau-associated neurodegeneration in AD.

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GSK-3β deletion in dentate gyrus excitatory neuron impairs synaptic plasticity and memory

Cited by 37 publications

References 69 publications

Differentially Expressed Genes in the Brain of Aging Mice With Cognitive Alteration and Depression- and Anxiety-Like Behaviors

Differentially Expressed Genes in the Brain of Aging Mice With Cognitive Alteration and Depression- and Anxiety-Like Behaviors

Magnolol Ameliorates Behavioral Impairments and Neuropathology in a Transgenic Mouse Model of Alzheimer’s Disease

Nature of Tau-Associated Neurodegeneration and the Molecular Mechanisms

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