Nhe5 deficiency enhances learning and memory via upregulating Bdnf/TrkB signaling in mice

Chen, Xuejiao; Wang, Xiyi; Tang, Lian; Wang, Jinjin; Shen, Chunling; Li, Jianbing; Shen, Lu; Zhang, Hongxin; Kuang, Ying; Fei, Jian; Wang, Zhugang

doi:10.1002/ajmg.b.32600

Cited by 27 publications

(15 citation statements)

References 38 publications

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“…However, the role of NO in each step of learning appears controversial and it might be task-dependent. ERK cascade is positively implicated in the development of fear conditioning, conditioned taste aversion memory, spatial memory, step-down inhibitory avoidance and object recognition memory ( Giovannini, 2006 ; Chen et al, 2017 ; Vithayathil et al, 2017 ). In our study, this pathway resulted to be activated upon cell exposure to GUA.…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders

et al. 2018

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Mounting evidence suggests that the guanine-based purines stand out as key player in cell metabolism and in several models of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. Guanosine (GUO) and guanine (GUA) are extracellular signaling molecules derived from the breakdown of the correspondent nucleotide, GTP, and their intracellular and extracellular levels are regulated by the fine-tuned activity of two major enzymes, purine nucleoside phosphorylase (PNP) and guanine deaminase (GDA). Noteworthy, GUO and GUA, seem to play opposite roles in the modulation of cognitive functions, such as learning and memory. Indeed GUO, despite exerting neuroprotective, anti-apoptotic and neurotrophic effects, causes a decay of cognitive activities, whereas GUA administration in rats results in working memory improvement (prevented by L-NAME pre-treatment). This study was designed to investigate, in a model of SH-SY5Y neuroblastoma cell line, the signal transduction pathway activated by extracellular GUA. Altogether, our results showed that: (i) in addition to an enhanced phosphorylation of ASK1, p38 and JNK, likely linked to a non-massive and transient ROS production, the PKB/NO/sGC/cGMP/PKG/ERK cascade seems to be the main signaling pathway elicited by extracellular GUA; (ii) the activation of this pathway occurs in a pertussis-toxin sensitive manner, thus suggesting the involvement of a putative G protein coupled receptor; (iii) the GUA-induced NO production, strongly reduced by cell pre-treatment with L-NAME, is negatively modulated by the EPAC-cAMP-CaMKII pathway, which causes the over-expression of GDA that, in turn, reduces the levels of GUA. These molecular mechanisms activated by GUA may be useful to support our previous observation showing that GUA improves learning and memory functions through the stimulation of NO signaling pathway, and underscore the therapeutic potential of oral administration of guanine for treating memory-related disorders.

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Section: Discussionmentioning

confidence: 99%

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders

et al. 2018

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“…TrkB-PLC/IP3 pathway on the inflammatory development of colitis. However, because the upstream BDNF of TrkB-PLC/IP3 pathway can improve the content of TNF-α and other inflammatory factor in depression, we speculated that the TrkB-PLC/IP3 pathway, as the downstream effector of BDNF, could also inhibit the inflammatory development in colitis [25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Effect of TrkB-PLC/IP3 pathway on intestinal inflammatory factors and enterocyte apoptosis in mice with colitis

Sun

et al. 2020

Preprint

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Background This study aimed to explore the effect of TrkB-PLC/IP3 pathway on intestinal inflammatory factors and enterocyte apoptosis in mice with colitis.Methods Forty 8-week SPF C57BL/6J mice were randomly and averagely divided into normal group (healthy mice), control group (sham-operated mice), model group (model mice without any treatment), and K252a group (model mice with the treatment of 100 μmoL/kg TrkB-PLC/IP3 pathway inhibitor for 5 d before clysis). Mice in model and K252a groups were used to establish ulcerative colitis models after medication.Results There were no significant changes of the content of serum tumor necrosis factor-α (TNF-α) and TNF-γ and protein expressions of TNF-α and TNF-γ in the colon tissues (all P >0.05), a significant increase of disease activity index, colon mucosa damage index, tissue damage index scores, content and protein expressions of serum interleukin-4 (IL-4) and IL-8, and a significant decrease of content and protein expressions of serum IL-10 (all P <0.05) in model and K252a groups, as compared to normal and control groups. Mice in model and K252a groups had blocked enterocyte cycle progression, raised apoptosis ratio, significantly increased mRNA and protein expressions of Caspase3, Bax, FasL and Fas, and significantly reduced mRNA and protein expressions of p-TrkB, PLC-γ1, IP3 and Bcl-2 (all P <0.05). Moreover, intestinal inflammation and apoptosis induced by colitis in K252a group became more aggravated through the inhibition of TrkB-PLC/IP3 pathway activity.Conclusions Inhibition of TrkB-PLC/IP3 pathway can promote the expression of intestinal inflammatory factors and enterocyte apoptosis in mice with colitis.

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“…Consistent with this hypothesis, BDNF and TrkB were widely located in the axon terminals (presynaptic sites) and dendrites (postsynaptic sites) of hippocampal neurons. The distribution and expression of synaptic proteins, such as SYN and PSD95, may be modulated by BDNF/TrkB signaling ( Jovanovic et al, 2000 ; Chen et al, 2017 ). It is well known that pCREB regulates the transcription of downstream genes including BDNF ( Reichardt, 2006 ; Lopez de Armentia et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that BDNF/TrkB signaling is attenuated in the early stages of AD. Thus, the expression of SYN and PSD95 in the hippocampus may be increased by enhanced BDNF/TrkB signaling ( Chen et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Long-Term DL-3-n-Butylphthalide Treatment Alleviates Cognitive Impairment Correlate With Improving Synaptic Plasticity in SAMP8 Mice

Han

et al. 2018

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is the most prevalent form of dementia worldwide. AD is characterized by mild cognitive impairment at onset, irreversibly progressing with age to severe neurodegeneration and cognitive deficits in the late stages. Unfortunately, no effective treatments exist to prevent or delay the cognitive symptoms of AD. Studies have shown that DL-3-n-butylphthalide (DL-NBP) alleviates cognitive impairment induced by amyloid-β in mice by reducing oxidative stress, inhibiting apoptosis, and decreasing tau phosphorylation. In this study, we examined the effects of DL-NBP administration on cognitive function in the senescence-accelerated mouse prone 8 (SAMP8) model of age-related dementia. DL-NBP treatment for 3 months alleviated cognitive impairment in SAMP8 mice as assessed by performance in the Morris water maze test. Moreover, DL-NBP significantly increased the expression of synaptophysin and postsynaptic density protein 95 in the hippocampus of SAMP8 mice, indicative of a protective effect on hippocampal structural synaptic plasticity. In addition, brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling, previously shown to promote synaptic plasticity, was significantly enhanced by the DL-NBP administration. Our findings suggest that DL-NBP is a potential drug candidate for the treatment of cognitive impairment in AD and may serve as the foundation for further research into the development of AD drugs.

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Nhe5 deficiency enhances learning and memory via upregulating Bdnf/TrkB signaling in mice

Cited by 27 publications

References 38 publications

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders

Effect of TrkB-PLC/IP3 pathway on intestinal inflammatory factors and enterocyte apoptosis in mice with colitis

Long-Term DL-3-n-Butylphthalide Treatment Alleviates Cognitive Impairment Correlate With Improving Synaptic Plasticity in SAMP8 Mice

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