Akt3 deletion in mice impairs spatial cognition and hippocampal <scp>CA</scp>1 long long‐term potentiation through downregulation of <scp>mTOR</scp>

Zhang, Tingting; Shi, Zhang; Wang, Ya; Zhang, Baofeng; Chen, Guiquan; Wan, Qi; Chen, Ling

doi:10.1111/apha.13167

Cited by 22 publications

(18 citation statements)

References 51 publications

(125 reference statements)

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“…miRNAs are involved in the development of various human disease by regulating their target genes (42). In the present study, a number of candidate target genes were predicted using TargetScan for miR-150, and AKT3 was selected based on previous studies demonstrating its crucial role in neurological function (43,44). AKT3 is a major isoform of the AKT family of serine/threonine protein kinases, which is predominant in the brain (45).…”

Section: Discussionmentioning

confidence: 99%

“…AKT3 is a major isoform of the AKT family of serine/threonine protein kinases, which is predominant in the brain (45). The dysregulation of AKT3 has been widely reported to be involved in the regulation of learning and memory deficits in several diseases (43,44). Additionally, AKT3 has been shown to be a target gene of miR-150 (19), which is one of the major molecules of the PI3K/AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

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Tetramethylpyrazine ameliorates isoflurane‑induced cognitive dysfunction by inhibiting neuroinflammation via miR‑150 in rats

Cui¹,

Zhang²,

Qu³

2020

Exp Ther Med

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Tetramethylpyrazine (TMP) has neuroprotective effects in the pathogenesis of some human diseases, such as Parkinson's disease. The present study aimed to investigate the role of TMP in isoflurane-induced cognitive dysfunction in rats, and further identify the mechanisms involved in the protective effects of TMP. The Morris water maze test was used to evaluate the cognitive function of rats exposed to isoflurane or treated with TMP. ELISA was conducted to evaluate the effects of isoflurane or TMP on neuroinflammation. The expression of microRNA-150 (miR-150) was measured using reverse transcription-quantitative PCR, and the potential target genes of miR-150 were predicted and verified. The impaired cognitive function induced by isoflurane in the rats was significantly ameliorated by treatment with TMP. In addition, TMP treatment in rats attenuated neuroinflammation caused by isoflurane. The expression of miR-150 was inhibited by isoflurane exposure, but was enhanced by TMP treatment in rats. Furthermore, the overexpression of miR-150 alleviated the isoflurane-induced cognitive dysfunction and neuroinflammation, while the neuroprotective effects of TMP were significantly abrogated by the knockdown of miR-150. AKT3 was a direct target of miR-150, and its mRNA expression was significantly decreased by the overexpression of miR-150 in isoflurane-and TMP-treated rats. These results demonstrated the protective effects of TMP against isoflurane-induced cognitive dysfunction, which were achieved by attenuating neuroinflammation via the regulation of the miR-150/AKT3 pathway. In addition, miR-150 may serve as a novel therapeutic target for the alleviation of cognitive dysfunction induced by anesthetics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine ameliorates isoflurane‑induced cognitive dysfunction by inhibiting neuroinflammation via miR‑150 in rats

Cui¹,

Zhang²,

Qu³

2020

Exp Ther Med

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“…No statistical method was employed to predetermine the sample size and the number of mice used in this study was determined based on statistical, experimental requirements, and our previous studies (Sha et al, 2016;Zhang et al, 2019). In this study, Akt3-WT mice…”

Section: Experimental Groups and Samples Sizesmentioning

confidence: 99%

“…Akt signaling has been found as upstream of the mammalian target of rapamycin (mTOR). The level of mTOR phosphorylation is selectively attenuated in the hippocampus of Akt3‐KO mice (Zhang et al., 2019). Inhibition of mTOR activity can reduce the proliferation of progenitor cells in the adult hippocampus (Romine et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Akt3‐mTOR regulates hippocampal neurogenesis in adult mouse

Zhang

Ding

Wang

et al. 2021

Journal of Neurochemistry

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Akt signaling has been associated with adult neurogenesis in the hippocampal dentate gyrus (DG). We reported cognitive dysfunction in Akt3 knockout (Akt3-KO) mice with the down-regulation of mTOR activation. However, little is known about the effects of Akt3 signaling on hippocampal neurogenesis. Herein, we show that progenitor cells, neuroblasts, and mature newborn neurons in hippocampal DG expressed Akt3 protein. The Akt3 phosphorylation in hippocampal DG was increased after voluntary wheel running for 7 days in wild-type mice (running WT mice), but not in Akt3-KO mice (running Akt3-KO mice). Subsequently, we observed that the proliferation of progenitor cells was suppressed in Akt3-KO mice and the mTOR inhibitor rapamycin-treated mice, whereas enhanced in running WT mice rather than running Akt3-KO mice. Neurite growth of neuroblasts was impaired in Akt3-KO mice and rapamycin-treated mice. In contrast, neither differentiation of progenitor cells nor migrating of newly generated neurons was altered in Akt3-KO mice or running WT mice. The levels of p70S6K and 4EBP1 phosphorylation were declined in Akt3-KO mice and elevated in running WT mice depending on mTOR activation. Furthermore, telomerase activity, telomere length, and expression of telomerase reverse transcriptase (TERT) were decreased in Akt3-KO mice but increased in running WT mice rather than running Akt3-KO mice, which required the mTOR activation. The study provides in vivo evidence that Akt3-mTOR signaling plays an important role in the proliferation of progenitor cells and neurite growth through positive regulated TERT expression and activation of p70S6K and 4EBP1.

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“…Thus, the insulin/PI3K/AKT/mTOR pathway importantly modulates neuronal plasticity underlying high cognitive functions. In fact, it was recently reported that AKT3 knockout mice exhibit microcephaly, cognitive defects, and reduced protein synthesis in response to long-term potentiation (LTP) via inactivation of mTOR and reduced protein synthesis necessary to sustain plasticity changes [43]. Different isoforms of PI3K have been implicated in synaptic plasticity and cognitive functions.…”

Section: Pi3k Signaling In Neuronal Metabolismmentioning

confidence: 99%

PI3K Signaling in Neurons: A Central Node for the Control of Multiple Functions

Sánchez-Alegría

Flores-León

Ávila-Muñoz

et al. 2018

IJMS

125

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Phosphoinositide 3-kinase (PI3K) signaling contributes to a variety of processes, mediating many aspects of cellular function, including nutrient uptake, anabolic reactions, cell growth, proliferation, and survival. Less is known regarding its critical role in neuronal physiology, neuronal metabolism, tissue homeostasis, and the control of gene expression in the central nervous system in healthy and diseased states. The aim of the present work is to review cumulative evidence regarding the participation of PI3K pathways in neuronal function, focusing on their role in neuronal metabolism and transcriptional regulation of genes involved in neuronal maintenance and plasticity or on the expression of pathological hallmarks associated with neurodegeneration.

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Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long‐term potentiation through downregulation of mTOR

Abstract: The Akt3 deficiency via inactivation of mTOR suppresses HFS × 4-induced mTOR-p70S6K signalling to reduce phosphorylation of 4EBP and eIF4E, which impairs protein synthesis-dependent long-LTP and long-term spatial cognitive function.

Cited by 22 publications

References 51 publications

Tetramethylpyrazine ameliorates isoflurane‑induced cognitive dysfunction by inhibiting neuroinflammation via miR‑150 in rats

Tetramethylpyrazine ameliorates isoflurane‑induced cognitive dysfunction by inhibiting neuroinflammation via miR‑150 in rats

Akt3‐mTOR regulates hippocampal neurogenesis in adult mouse

PI3K Signaling in Neurons: A Central Node for the Control of Multiple Functions

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