|Year : 2021 | Volume
| Issue : 6 | Page : 266-273
Nicotinamide adenine dinucleotide promotes synaptic plasticity gene expression through regulation N-methyl-D-aspartate receptor/Ca2+/Erk1/2 pathway
Xiao-Yu Liu1, Rui-Heng Song1, Tao Li2, Xu Tan1, Xiang-Hong Zhang3, Kun-Kun Pang4, Jian-Yu Shen1, Qing-Wei Yue1, Jin-Hao Sun1
1 Department of Anatomy, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
2 Department of Neurosurgery, The Third Affiliated Hospital of Shandong First Medical University, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China
3 Morphological Experimental Center, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
4 Department of Uitrasound, Second Hospital of Shandong University, Jinan, Shandong, China
|Date of Submission||01-Jun-2021|
|Date of Decision||25-Aug-2021|
|Date of Acceptance||30-Nov-2021|
|Date of Web Publication||27-Dec-2021|
Dr. Jin-Hao Sun
Department of Anatomy and Neurobiology, School of Basic Medicine, Shandong University, Jinan 250012, Shandong
Source of Support: None, Conflict of Interest: None
Nicotinamide adenine dinucleotide (NADH) has been reported to regulate synaptic plasticity recently, while its role in this process remains unclear. To explore the contribution and the underlying mechanisms of NADH regulating synaptic plasticity, here, we examined NADH's effect on immediate-early response genes (IEGs) expressions, including C-Fos and Arc in primary cultured cortical neurons and the frontal cortex of mouse brain. Our results showed that NADH promoted IEGs expression and that the C-Fos and Arc levels are increased in primary cultured cortical neurons, which is almost completely blocked by N-methyl-D-aspartate receptor (NMDAR) inhibitor, MK-801. Moreover, NADH significantly increased intracellular Ca2+ levels and the phosphorylation of Erk1/2, a downstream molecule of the NMDAR. Furthermore, NADH also significantly increased IEGs expression in vivo, accompanied by the changes of Ca2+ in neurons and activation of excitatory neurons in the mouse frontal cortex. In conclusion, this study indicates that NADH can promote the expression of synaptic plasticity-related IEGs through the NMDAR/Ca2+/Erk1/2 pathway, which provides a new way to understand the regulatory role of NADH in synaptic plasticity.
Keywords: Immediate early gene, neuron, nicotinamide adenine dinucleotide, synaptic plasticity
|How to cite this article:|
Liu XY, Song RH, Li T, Tan X, Zhang XH, Pang KK, Shen JY, Yue QW, Sun JH. Nicotinamide adenine dinucleotide promotes synaptic plasticity gene expression through regulation N-methyl-D-aspartate receptor/Ca2+/Erk1/2 pathway. Chin J Physiol 2021;64:266-73
|How to cite this URL:|
Liu XY, Song RH, Li T, Tan X, Zhang XH, Pang KK, Shen JY, Yue QW, Sun JH. Nicotinamide adenine dinucleotide promotes synaptic plasticity gene expression through regulation N-methyl-D-aspartate receptor/Ca2+/Erk1/2 pathway. Chin J Physiol [serial online] 2021 [cited 2022 Jan 24];64:266-73. Available from: https://www.cjphysiology.org/text.asp?2021/64/6/266/333797
Xiao-Yu Liu and Rui-Heng Song contributed equally to this work.
| Introduction|| |
Synaptic plasticity is the adaptive change in synaptic strength or efficacy of neurons experiencing different environmental changes. It has been proved that synaptic plasticity is closely associated with learning and memory as well as various neurogenic and psychiatric disorders., The formation of synaptic plasticity is attributed to a variety of signaling molecules expression and receptors activation., It is well accepted that the activation of N-methyl-D-aspartate receptor (NMDAR) in the postsynaptic membrane of neurons plays an important role in synaptic plasticity. NMDARs activation triggers calcium influx and further activates a variety of protein kinases, such as Erk1/2, CaMKII, and PKA, which then promote the expression of genes associated with synaptic plasticity. Immediate early response genes (IEGs), including C-Fos, activity-regulated cytoskeleton-associated protein (Arc) participates the regulation of synaptic plasticity.,,, C-Fos is a nuclear protein transcription factor and often serves as a marker of neuronal activation. Arc can quickly accumulates at synaptically active sites in activated neuronal dendrites.
Nicotinamide adenine dinucleotide (NADH) can regulate the cellular redox state and energy metabolism.,, Recent studies have suggested that NADH is involved as a signaling molecule in the regulation of synaptic plasticity and the expression of associated IEGs. First, regulation of NADH/NAD+ biosynthesis alters the synaptic plasticity. For example, nicotinamide phosphoribosyltransferase (Nampt) is required for the synthesis of NADH/NAD+, in Nampt knockout mice, the long-term depression and the function of learning and memory are significantly impaired., Second, NAD+-dependent deacetylase, silencing information regulator 1, directly promotes neuronal synaptic plasticity., Recent studies have also demonstrate that lactate regulates synaptic plasticity through NADH, rather than pyruvate for signaling synaptic plasticity., These studies suggest that NADH may act as a signaling molecule to regulate synaptic plasticity. However, the underlying mechanisms are largely unclear until now.
To identify possible mechanisms by which NADH regulates synaptic plasticity in neurons, we first detected the effect of NADH on the expression of IEGs in cultured neurons and then analyzed the role of NMDAR and Ca2+ in this process. Moreover, the genetically encoded calcium indicator virus GCaMP6f was injected into the cerebral cortex to detect the changes in Ca2+ signaling. In order to further determine the effects of NADH on neurons in vivo, a viral vector containing the C-Fos promoter was injected into the brain and the activation of excitatory neurons by NADH was examined. This study will provide a novel mechanism by which NADH regulates synaptic plasticity in neurons.
| Materials and Methods|| |
Adult C57BL/6 mice (6–8 weeks) were provided by the Laboratory Animal Center of Shandong University. The experimental procedures were carried out based on the Institutional Animal Care and Use Committee of Shandong University. The mice were housed in normal 12 h light and 12 h dark environments, with free access to water and food.
Cell culture and treatment
The primary cortical neurons were cultured as before with minor modification. Briefly, the cerebral cortex of neonatal mice (day 0 or 1 after birth) was collected and digested with 0.25% trypsin for 10 min at 37°C. The collected cells were then incubated on cultured plates with medium containing 90% DMEM/F12 and 10% fetal bovine serum, and after approximately 4–6 h were replaced to maintenance medium containing 1% B27, 1% glutamine, and 1% penicillin/streptomycin. After 48 h, cytarabine was added into the culture medium to inhibit the growth of glial cell. On day 5 of in vitro culture, neurons were treated with drugs for the following experiments. Drugs contained different concentrations of NADH (1, 2, 4, 8, 10, 12, 16 mM), or together with MK-801 (40 mM) or U0126 (10 μM).
RNA extraction and real-time quantitative PCR
The fast 200 kit (Fastagen, Shanghai, China) was used to extract total RNA from cultured neurons and tissues, and the Nanodrop was used to test the concentration and purity of the RNA. RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific, USA) was used for reverse transcription. Moreover, reverse transcription polymerase chain reaction was performed with UltraSYBR Mixture (Kang Wei, China) at 40 cycles, 95°C for 15 s and 60°C for 1 min. Primer sequences were designed as follows: Arc: 5′-CCA GTC TTG GGC AGC ATA GC-3′ and 5′-TCT GCT CTT CTT CAC TGG TAT GAA TC-3′; C-Fos, F: 5′-CGG AGG AGG GAG CTG ACA-3′, R: 5′-CTG CAA CGC AGA CTT CTC ATC T-3′; GAPDH, F: 5′-AAA TGG TGA AGG TCG GTG TG-3′, R: 5′-GAA TTT GCC GTG AGT GGA GT-3′. All the data were used to quantitatively calculate the relative expression of genes by 2-△△Ct method.
Neurons from different groups of cultures were collected and lysed with RIPA lysis buffer supplemented with protease inhibitors for 30 min at 4°C. Then, the samples were centrifuged at 13000 rpm, 4°C for 15 min. The supernatant was collected and boiled in a loading buffer. Protein concentration was measured using a BCA reagent (Thermo Scientific, USA) and then transferred to a polyvinylidene difluoride (PVDF) membrane. The membrane was then incubated overnight at 4°C with following primary antibodies: anti-Fos (1:1000, #AF0132, Affinity), anti-Arc (1:250, #sc-17839, Santa Cruz), and anti-GAPDH (1:1000, #AF7021, Affinity). Immunoglobulin G horseradish peroxidase (HRP)-labeled secondary antibodies (1:5000) were then applied at the room temperature for additional 2 h. Millipore's enhanced chemiluminescence was used to visualize the proteins. The data were analyzed using ImageJ software (National Institutes of Health, Bethesda, MD, USA).
Primary cerebral cortical neurons were cultured in six-well plates at a density of 2 × 104/cm2. After treatment with different drugs for 24 h, they were observed under an inverted phase-contrast microscope. Five visual fields were randomly selected in each group of cells for sholl analysis a previous report. According to the scale of the picture, a series of concentric circles, 10−200 μm in diameter were drawn with the cell body of the neuron as the center of the circle. The number of intersections of each circle with neurites was then counted and analyzed.
Calcium time course detection
The fluorescent probe Fluo-4 AM was used to detect intracellular calcium concentrations. First, the culture medium was removed and the Fluo-4 AM working solution was added into the 24-well plate, which were then incubated at 37°C for 30 min. After washed with HBSS three times, the cells were recorded by a Zeiss laser confocal microscope to detect the intracellular calcium concentrations. The detection wavelength was 488 nm and the total detection time for each group was 700 s. The Veh or MK-801 was added at -200 s and NADH was added at 0 s. Pictures of the neurons were taken every 10 s and the captured fluorescence intensity was analyzed via ZEN software.
Viral vector injection
Mice were anesthetized by intraperitoneal injection of 5% chloral hydrate with the dosage of 0.75 ml/100 g and then stereotaxicly fixed on a brain apparatus with the skull placed horizontally. The position of the target brain region was determined from the mouse brain map. The coordinates of the frontal cortex were as follows: 0.1 mm posterior to bregma, 2 mm lateral to bregma, and 2 mm inferior to the skull. 0.5 μl of the virus was aspirated with a needle and slowly injected into the brain. The injection took approximately 5 min and the needle was kept for additional 5 min. Two vectors were used in the experiment. The vector of pAAV-hSyn1-GCaMP6f-P2A-nls-dTomato indicated the activity of calcium ions, and GV581, a vector containing the C-Fos promoter, reflected neuron activation. 14 days later, NADH was injected at the same coordinates to determine the changes of Ca2+ and cellular activation in vivo.
The statistical analysis of all data in this experiment was completed by the software GraphPad Prism, and the data were expressed in the form of mean ± standard deviation. The comparison between the two groups was made using the independent samples t-test, and comparison between multiple groups was made using one-way ANOVA and Bonferroni posttest. P < 0.05 was considered statistically significant.
| Results|| |
Nicotinamide adenine dinucleotide promotes immediate-early response genes expression of primary cortical neurons
Different concentrations of NADH (1, 2, 4, 8, 10, 12, and 16 mM) were applied to primary cortical neurons. The messenger RNA (mRNA) expression levels of IEGs, including C-Fos, and Arc were detected after 1 h of NADH treatment. The results showed that NADH obviously promoted the expression of C-Fos and Arc in cultured neurons in a concentration-dependent manner as compared to the control group with the expression reaches a peak at 8 mM [Figure 1]a and [Figure 1]b. Therefore, 8 mM NADH was an effective concentration for inducing IEGs expressions.
|Figure 1: Nicotinamide adenine dinucleotide promotes the expression of immediate-early response genes. (a and b) The expression of immediate-early response genes in primary cutured neurons was detected after treatment with different concentrations of nicotinamide adenine dinucleotide for 1 h. (c and d) The expression of immediate-early response genes was detected when treated with 8 mM nicotinamide adenine dinucleotide at different times. (e-g) Representative western blots and statistical analysis of protein expression. The data were obtained by one-way ANOVA and Bonferroni post-test. *P < 0.05, **P < 0.01, ***P < 0.001, (n = 3).|
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Next, in order to determine the appropriate time for the action of NADH, we collected the neurons treated with 8 mM NADH after 20, 40, 60, 120, and 240 min, respectively. The data showed that IEGs levels gradually increased with the time extension and reached a peak at about 60 min. At 120 min, IEGs expression decreased and C-Fos mRNA showed no significant difference compared to the initial level [Figure 1]c, (P> 0.05), while Arc remained higher than the initial levels [Figure 1]d, (P < 0.001). Moreover, the increase in protein levels of IEGs induced by NADH was consistent with the changes in mRNA. As shown in [Figure 1]e, [Figure 1]f, [Figure 1]g, the protein levels of C-Fos and Arc reached the peak when NADH was treated for 60 min. After 240 min, their protein levels returned to their original levels.
Inhibition of N-methyl-D-aspartate receptors blocks nicotinamide adenine dinucleotide promoting effect on immediate-early response genes expression
Next, we blocked NMDAR with MK-801 and investigated NADH's effects on IEGs expression. As shown in [Figure 2]a and [Figure 2]b, the mRNA expression of IEGs was significantly reduced after MK-801 treatment. Therefore, inhibition of NMDARs blocked the effect of NADH on IEGs expression. Similarly, the protein expression of both C-Fos and Arc was significantly reduced when co-administration with MK-801 and NADH [Figure 2]c, [Figure 2]d, [Figure 2]e, (both P < 0.01). Therefore, at the protein level, inhibition of NMDARs completely blocked NADH from promoting IEGs expressions.
|Figure 2: MK-801 inhibits nicotinamide adenine dinucleotide's effects on the expression of immediate-early response genes. 8 mM nicotinamide adenine dinucleotide and/or 40 μM MK-801 were added into the culture medium in the following groups: control group, nicotinamide adenine dinucleotide group, MK-801 group, nicotinamide adenine dinucleotide and MK-801 co-treatment group. (a and b) The mRNA expression levels of immediate-early response genes under different treatments. (c-e) Representative western blottings and quantitative analysis results of protein levels of immediate-early response genes. The data were obtained by one-way ANOVA combined with Bonferroni post hoc test. **P < 0.01, ***P < 0.001, (n = 3).|
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Inhibition of N-methyl-D-aspartate receptors with MK-801 reduces neuronal intersections
From the morphological observation [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, several neurites were visible and connected to each other in a network in the control group. When treated with MK-801, the number of neurites decreased significantly. The drawing of neuron profile was also presented [Figure 3]e, [Figure 3]f, [Figure 3]g, [Figure 3]h. The sholl analysis was performed and the data showed that MK-801 obviously inhibited neurites growth and decreased the number of neuronal intersections compared to the control [Figure 3]i and [Figure 3]j, (P < 0.05), whereas co-treatment of MK-801 with NADH might increase neuron intersections [Figure 3]i and [Figure 3]j, (P < 0.05). However, the intersections of NADH group showed no statistical difference with the control. The above results indicated that MK-801 inhibited the neurites growth, while NADH attenuated the MK-801's effects.
|Figure 3: Sholl analysis of neurites and branches of cultured neurons after nicotinamide adenine dinucleotide and/or MK-801 treatment. Photographs were taken 24 h later after drug treatment. (a-d) Typical images of different groups of neurons obtained by drawing a series of concentric circles with a diameter of 10-200 μm, centred on cell body. (e-h) Drawing of neurons from different groups. (i) The number of intersections of concentric circles with neurites. (j) The total number of intersections in different groups was analyzed. Data were obtained through one-way ANOVA combined with bonferroni post hoc test analysis. *P < 0.05, **P < 0.01, (n = 5). Bar, 20 μm.|
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Nicotinamide adenine dinucleotide promotes immediate-early response genes expression through regulating Ca2+ signaling and Erk1/2 activity
Since NADH promotes the expression of IEGs through NMDARs, and activation of NMDARs can promote Ca2+ influx, does NADH affect the level of Ca2+ in neurons? We performed a Ca2+ time course detection in cultured cells [Figure 4]a. The data showed that Ca2+ signals were weak in cultured neurons before NADH treatment. When 8 mM NADH was applied at 0 s, the fluorescence signal of Ca2+ significantly increased. Moreover, the Ca2+ signal gradually increased within 500 s after NADH treatment [Figure 4]b. Moreover, Erk1/2 is a downstream signaling molecule of the NMDAR. The data showed that NADH significantly increased p-Erk1/2 level in cultured neurons [Figure 4]c and [Figure 4]d, (P < 0.05). Does Erk1/2 also regulate IEGs expression? We added U0126 (10 μM) into culture medium to specifically inhibit Erk1/2 activity. The results showed that inhibition of Erk1/2 blocked IEGs expressions at the mRNA level [Figure 4]e and [Figure 4]f. Similarly, the protein levels of C-Foc and Arc were also decreased when Erk1/2 activity was inhibited [Figure 4]g, [Figure 4]h, [Figure 4]i.
|Figure 4: Nicotinamide adenine dinucleotide increased intracellular Ca2+ levels and inhibition of Erk1/2 activity in cultured neurons. (a) Real-time trajectory of fluorescence intensity (n = 18). (b) Detection Ca2+ levels by adding MK-801 (40 μM) 200s before nicotinamide adenine dinucleotide treatment (n = 32). (c and d) nicotinamide adenine dinucleotide up-regulated the expression of p-Erk1/2 (n = 3). (e-i) The mRNA and protein expression levels of immediate-early response genes under different treatments, respectively. Inhibition of Erk1/2 activity blocked the nicotinamide adenine dinucleotide's effects on the expression of immediate-early response genes. Data in d were obtained by unpaired t-test. Data in panels (e and f, h and i) were obtained by one-way ANOVA combined with bonferroni post-test. *P < 0.05, **P < 0.01, ***P < 0.001 (n = 3).|
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Nicotinamide adenine dinucleotide promotes immediate-early response genes expression and neuronal Ca2+ signaling of frontal cortex in mice
Next, we injected 8 mM NADH into the frontal cortex of mice to detect IEGs expression in vivo. The results showed a significant increase in C-Fos and Arc mRNA levels, which were 6.3-fold and 5.9-fold, respectively, of the control groups [Figure 5]a, (both P < 0.05). Moreover, viral vectors containing GCaMP6 Ca2+ indicator were injected into the frontal cortex of mouse brains to measure neuronal Ca2+ signal changes. After 14 d of viral vector transfection, 8 mM NADH or normal saline was injected at the same position, and brains were collected 1 h later. The fluorescence of NADH group was stronger than that of the control group [Figure 5]b, [Figure 5]c, [Figure 5]d, (P < 0.001). Furthermore, another viral vector GV581 containing C-Fos promoter was also injected into the frontal cortex. 14 d later, 8 mM NADH was injected at the same location of the brain. The data showed that the fluorescence of NADH group was also stronger than that of the control group [Figure 5]e, [Figure 5]f, [Figure 5]g, (P < 0.05). These data indicated that NADH increased C-Fos expression and significantly promoted neuron activation.
|Figure 5: Nicotinamide adenine dinucleotide promotes the expression of immediate-early response genes and increases neuronal Ca2+ levels in the frontal cortex of mice. (a) Injection of 8 mM nicotinamide adenine dinucleotide into the frontal cortex of mice obviously promoted the expression of C-Fos and Arc (n = 3). (b and c) Typical pictures of brain slices from the control and nicotinamide adenine dinucleotide groups after injection of AAV-GCaMP6. (d) Fluorescence intensity analysis of vector injection (n = 6). (e and f) Typical pictures of brain slices from control and nicotinamide adenine dinucleotide groups injected with GV581 containing the C-Fos promoter. (g) Fluorescence intensity analysis of GV581 injection (n = 6). The data in a were obtained by one-way ANOVA and bonferroni post-test. Data in d and g were obtained by unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001. Scale = 200 μm.|
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| Discussion|| |
In this study, we investigated the effect of NADH on the expression of IEGs and analyzed the underlying mechanisms. Our data showed that NADH significantly increased the expression of C-Fos and Arc. At the same time, NADH increased Ca2+ levels and promoted Erk1/2's phosphorylation. Moreover, blocking NMDAR and inhibiting Erk1/2 both obviously inhibited NADH's promotion on the expression of IEGs. Furthermore, we demonstrated that NADH could increase the expression of IEGs, Ca2+ levels, and neuronal activation in frontal cortex of the mouse brain.
Our results indicated that NADH increased the expression of C-Fos and Arc in a concentration and time-dependent pattern. A previous study also suggested that NADH can promote the expression of some early response genes while they did not perform in-depth analysis. They cultivated fetal mouse cerebral cortical neurons for up to 14 days. We cultured neonatal mouse cortical neurons for up to 5 days until the neurons had obvious neurite. Our study indicated that NADH significantly promoted the expression of IEGs in cultured neonatal mouse cortical neurons. Importantly, we also performed in vivo experiments to detect the effects of NADH. The data showed that NADH injected into the cortical cortex after 1 h could significantly promoted the expression of IEGs.
When treating cultured neurons with MK-801 to block NMDARs, the effect of NADH on the expression of IEGs was almost completely blocked, suggesting that NMDARs play a crucial role in the function of NADH. A low dose of MK-801 at10 μM can also block NMDARs in our previous study. Previous studies declared that NMDARs are the key molecules in the regulation of synaptic plasticity and play a critical role in long-term memory in many learning paradigms. The data of Sholl analysis showed that NADH slightly increased intersections of cultured neurons, although there was no statistical difference. Surprisingly, NDAH co-administrated with MK-801 showed a slight increase in intersection points. Possibly, NADH plays a direct role in the regulation of structural plasticity despite the blockade of NMDARs. Indeed, NAD could improve the neurites growth.
The role of NADH may be related to the redox state of cells. NADH is a molecule produced during cellular energy metabolism and can be generated during the transforming of lactate to pyruvate. Lactate induces the expression of plasticity associated genes in cultured cortical neurons by increasing NMDAR-induced Ca2+ influx. While NADH partly mimics the effects of lactate, NADH increases the intracellular NADH/NAD+ ratio, which in turn changes the intracellular redox state of neurons. The redox-sensitive NMDA regulatory site exists on the NR1 subunit, and NMDAR activity is stronger when the cell is in a reduced state. It may be speculated that after NADH increases the intracellular NADH/NAD+ ratio, neurons are in a reduced state, which in turn activates the NR1 subunit of the NMDAR, and then increases the activity of the NMDAR, triggering a series of physiological responses. A previous study has also reported that L-lactate, a upstream molecule of NADH, can specifically enhance the Ca2+ signaling levels caused by the synergistic effect of glutamate and glycine by activating of the N2B subunit of NMDAR. As a transmitter of cellular redox state, NADH acts on specific subunits of NMAD receptors, which needs to be further explored.
The effect of NADH on Ca2+ levels in cortical neurons was further detected by intracortical injection of the vector AAV-GCaMP6 in vivo, which indicated that NADH could enhance Ca2+ signals in cortical neurons. GCaMP6 is a novel calcium ion indicator that can accurately indicate the changes of calcium ion signals. Recently, a study on methamphetamine-induced changes in Ca2+ concentration also adopts a similar experimental method to record the changes in neuronal calcium signals. We also accurately detected changes in neuronal Ca2+ signals after NADH treatment in the experiment. Moreover, the results of GCaMP6 detection in vivo are consistent with those obtained with Fluo-4AM dye in cultured cells.
We also injected the GV581 viral vectors containing C-Fos promoter into the frontal cortex and detected neuronal activation in the brain when treated with NADH. The expression of C-Fos is considered to be an indicator of neuronal activation, which underlies many biological functions such as synaptic plasticity, learning, and memory.,, Injection of AVV-GV581 into the brain accurately reflects the regulatory effect of NADH on neuron activation and also provides reliable evidence that NADH regulates the expression of IEGs and alters synaptic plasticity.
| Conclusion|| |
Our studies indicate that NADH can promote the expression of IEGs both in vivo and in vitro and increases the intracellular Ca2+ in neurons by NMDAR/Ca2+/Erk1/2 pathway. This study provides an experimental basis for understanding NADH as a new signaling molecule involved in the regulation of synaptic plasticity.
The authors would like to thank Dr. Mei-Ling Wu for her kind help and the Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.
Financial support and sponsorship
The authors thank the supporting by a grant of Shandong Provincial Natural Science Foundation with No. ZR2012HM026 and a project of Jinan Science and Technology Bureau with No. 201907057.
Conflicts of interest
There are no conflicts of interest.
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