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Tenuigenin enhances hippocampal Schaffer collateral-CA1 synaptic transmission through modulating intracellular calcium.

ABSTRACT

Background: Tenuigenin (TEN), a natural product from the Chinese herb Polygala tenuifolia root, has been reported to improve cognitive function and exhibits neuroprotective effects in pharmacological studies of the central nervous system. Synaptic transmission is the essential process of brain physiological functions such as learning and memory formation, and TEN has been shown to facilitate the basic synaptic transmission. Hypothesis/Purpose: Although our previous work has demonstrated that TEN is able to potentiate the basic synaptic transmission, the potential mechanism remains unclear. Here we investigated the effect of TEN on the synaptic transmission and analysed the potential mechanism. We hope that these findings will contribute to explain the role of TEN as a nootropic product or neuroprotective drug in the future.

Methods: Field excitatory postsynaptic potentials (fEPSPs), spontaneous excitatory postsynaptic currents (sEPSCs) and miniature spontaneous excitatory postsynaptic currents (mEPSCs) were recorded, by using in vitro field potential electrophysiology and whole-cell patch clamp techniques in acute hippocampal slices from rats.

Results: TEN perfusion significantly enhanced the slope of fEPSPs and reduced the ratio of paired-pulse facilitation. Moreover, TEN increased the frequency and amplitude of sEPSCs but only improved the frequency of mEPSCs rather than amplitude in hippocampal CA1 pyramidal neurons. With removal of extracellular calcium, TEN treatment also enhanced the mEPSCs frequency without affecting amplitude. Interestingly, the increase of mEPSCs frequency caused by TEN was blocked by chelation of intracellular calcium with BAPTA-AM. Conclusion: These results indicate that TEN enhances the basic synaptic transmission via stimulating presynaptic intracellular calcium.

Keywords:

Tenuigenin

Synaptic transmission

Paired-pulse facilitation

Calcium

Introduction

The roots of Polygala tenuifolia Willd are used as a well-known traditional Chinese medicine administered to treat and prevent dementia. Tenuigenin (TEN) is an active component extracted from roots of Polygala tenuifolia Willd. Pharmacological data indicate that TEN could promote proliferation and differentiation in hippocampal neural stem cell (Chen et al. 2012), and protect cultured hippocampal neurons or SH-SY5Y cell against neurotoxicity (Chen et al. 2010; Liang et al. 2011). In term of cognitive function, previous studies have shown that TEN enhanced learning and memory in both healthy and ovariectomized mice, in which one of the potential mechanisms is related to improve the basic synaptic transmission and synaptic plasticity (Huang et al. 2013; Cai et al. 2013).

Synaptic transmission, the essential process in brain physiological functions, is critical in the signal integration activities of the central nervous system (CNS). Synaptic transmission is primarily based on the regulated release of neurotransmitter from synaptic vesicles (Heine 2012). When an action potential arrives at the presynaptic axonal terminal, depolarization opens voltage-gated [Ca.sup.2+] channels (VGCCs) and [Ca.sup.2+] influx triggers the fusion of synaptic vesicles docked and primed at the active zone of the presynaptic plasma membrane. Subsequently, neurotransmitter is released into the synaptic cleft and diffuses to the postsynaptic membrane to activate neurotransmitter receptors. Finally, synaptic vesicles are retrieved via endocytosis in order to restore the releasable vesicle pool (Littleton 2006; Ryan 2006; Evstratova and Toth 2014). Many cellular mechanisms could contribute to the change of basic synaptic transmission, including presynaptic transmitter release, and postsynaptic receptor quantity and efficacy.

Although TEN has been reported to improve the basic synaptic transmission in hippocampal brain slices of mice (Huang et al. 2013), the potential mechanism remains unknown. Therefore, in the present study, we examined the effect of TEN on the process of basic synaptic transmission in the CA1 region of hippocampal slices from rats and analyzed the potential mechanism, by using in vitro field potential electrophysiology and whole-cell voltage-damp recording techniques. Our findings would be rewarding for understanding the role of TEN on modulating the response of CNS such as nootropic and neuroprotective effects.

Materials and methods

Drugs and reagents

TEN (purity > 98%) was purchased from the National Institute of Pharmaceutical and Biological Products (Beijing, China). Other chemical reagents were purchased from Sigma (St. Louis, USA). TEN was dissolved in artificial cerebrospinal fluid (aCSF) at a concentration of 2 [micro]g/ml, and its efficacy was tested by bath perfusion (solution exchange was completed within 30 s). aCSF with added EGTA (0.5 mM) but without Ca[Cl.sub.2] was used as nominally [Ca.sup.2+]-free aCSF. BAPTA-AM (50 [micro]M) was loaded by bath application (Miura et al. 2012).

Animals

For the field excitatory postsynaptic potentials (fEPSPs) recording, three-month old male Sprague-Dawley rats (200-250 g) were obtained from the Sun Yat-sen University, China. In the whole-cell current recording, the hippocampal brain slices were prepared from 15 to 30 days old Sprague-Dawley rats as described previously (Yao et al. 2013). The animals were housed at 22 [+ or -] 3[degrees]C, 55 [+ or -] 5% humidity, and 12 h light/dark cycle from 08:00 to 20:00. All animals were given three days to adapt to this new environment before any procedure was initiated. Experimental procedures in this study were approved by the Committee on Animal Care and Usage of South China Normal University and conducted under National Institutes of Health guidelines (Guide for the Care and Use of Laboratory Animals, NIH publication 93 23, revised 1985).

Brain slices preparation

The method of brain slices preparation was slightly modified from those described previously (Huang et al. 2013; Yao et al. 2011). Briefly, acute hippocampal slices were prepared and maintained in an interface recording chamber containing preheated aCSF of the following composition (in mM): 117 NaCl, 4.7 KCl, 2.5 Ca[Cl.sub.2], 1.2 Mg[Cl.sub.2], 25 NaHC[O.sub.3], 1.2 Na[H.sub.2] P[O.sub.4], and 11 glucose and maintained at 31 [+ or -] 0.5[degrees]C, pH 7.35-7.45. Slices were continuously perfused with this solution at a rate of 1.5-2.0 ml/min while the surface of the slices was exposed to warm, humidified 95% 02/5% C[O.sub.2]. Recordings began after 100 min of incubation.

The slope of fEPSPs recording

The fEPSPs slope was recorded from CA1 stratum pyramidal cells using a single glass pipette filled with 2 M NaAc (yielding a resistance of 2-5 M[ohm]). A bipolar stimulation electrode (twisted nichrome wire, 0 140 [micro]m) was positioned at Schaffer collateral-commissural projections. Once the slope of fEPSPs has been maximized and stabilized, an input/output (I/O) curve was generated. The optimal stimulation intensity (0.3-1.0 mA, 0.1 ms in duration) was set at 40% of maximal I/O value through the experiment. After establishing a 15-20 min stable baseline, test compounds were introduced into the perfusion line by switching from control aCSF to drug-containing aCSF.

In the paired-pulse facilitation (PPF) experiment, two consecutive pulses were applied with a 50 ms inter-pulse interval. PPF quantification was carried out as the ratio of the fEPSPs slopes of the second response over that of the first response in each pair of stimuli. Recordings were collected after establishing a stable baseline for 15 min, and then the effect of TEN was tested by bath application for 15 min. Data were collected and analysed by LTP230D (WinLTP Ltd., Bristol, Britain) software.

The whole cell current recording

Recordings were performed in whole-cell voltage-clamp configuration as described previously (Yao et al. 2013). The resistance of the recording electrode was 3-5 M[ohm] when filled with intracellular solution. The intracellular solution was composed of the followings (mM): K-gluconate 140, Mg[Cl.sub.2] 2, Na-ATP 2, Na-GTP 0.2, EGTA 5, HEPES 10, pH 7.3. Osmolarity was adjusted to 320 mOsm with sucrose. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded under voltage-clamp at -70 mV from CA1 pyramidal neurons after blocking the GABAA receptors by using 30 [micro]M bicuculline. In preliminary experiments, all sEPSCs were blocked by CNQX and APV.

Miniature spontaneous excitatory postsynaptic currents (mEPSCs) were recorded under voltage-clamp at -70 mV by blocking action potentials with 1 [micro]M TTX. All drugs were bath-applied via a peristaltic pump. After whole cell access was achieved, the series resistance ([R.sub.s]) was partially compensated by the amplifier. Both input resistance and series resistance were monitored throughout the experiments. The recording was accepted only with the stable series-resistance ([less than or equal to] 20 M[ohm]) and input-resistance. To avoid the influence on the amplitude and the detection threshold of mEPSCs induced by [R.sub.s] change, [R.sub.s] was assessed during a period of experimental recordings. If the change exceeded 15% of the initial value, the data were excluded from the analysis. The peak amplitude of inward currents was given as magnitudes. After the recorded neuronal cell was allowed to stabilize for 5-10 min, the effect of TEN was tested by bath perfusion for 60 s. Data were acquired by Clampex 9.2 (Molecular Devices, Sunnyvale, CA, USA) via a digidata 1322 series A/D board set to a sampling frequency of 10 kHz.

Statistical analysis

Data were expressed as mean [+ or -] SD. The slope of fEPSPs was expressed as percentage changes from baseline and statistically analyzed by two-way ANOVA, with treatment and time as factors (Yan et al. 2014; Liu et al. 2014). Paired-pulse ratio (PPR) was expressed as the slope of 2nd fEPSPs/1st fEPSPs and statistically analyzed by one-way ANOVA.

To detect sEPSCs and mEPSCs, a detection threshold was set at three times the root mean square of the baseline noise. After detection, the frequency and peak amplitude of sEPSCs from individual neurons were analyzed. Each detected event from the 20 to 30 min recording session was visually inspected to remove false detections. Miniature synaptic events of mEPSCs were counted and analyzed using Mini Analysis software (version 6.0.3; Synaptosoft, Decatur, GA, USA) and Igor 6.0 (OriginLab, Northampton, MA, USA). Frequencies were calculated by dividing the total number of mEPSCs events by the total time sampled. Paired Student's t test was used to compare two independent groups. Differences between the groups were considered to be statistically significant when two-tail p value < 0.05.

Results

TEN enhances the basic synaptic transmission in brain slices of rats

According to the previous study (Huang et al. 2013), the effect of TEN on the basal synaptic transmission was investigated at the dose of 2 [micro]g/ml in the hippocampal slices of rats. As shown in Fig. 1A and B, after 15 min of stable baseline recordings with control aCSF, the fEPSPs slope was reversibly improved with TEN-containing aCSF for 15 min. The effect caused by TEN possessed a rapid onset and persisted for approximately 50 min, and then recovered to the baseline level after washout. The maximal increase in the fEPSPs slope was achieved at about 10 min after TEN treatment. These findings indicate that 2 [micro]g/ml TEN could reversibly improve the basal synaptic transmission.

TEN decreases the ratio of PPF in the basic synaptic transmission

We firstly examined the effect of paired-pulse stimuli (PPS) on the hippocampal slices with control aCSF. As shown in Fig. 2A and C, we observed that there was a rapid growth in the second fEPSPs slope after PPS at an interval of 50 ms, and then obtained a PPF and a stable PPR during 50 min recordings. Interestingly, the first fEPSPs slope exhibited a rapid onset and persisted for about 50 min after application of TEN-aCSF for 15 min, and then restored to the baseline level after washout. In spite of the second fEPSPs slope enjoyed a slight enhancement, the obvious improvement in the first fEPSPs was observed and thus associated with a significant reduction in PPR (p < 0.01) (Fig. 2A-C), showing that 2 [micro]g/ml TEN decreased the ratio of PPF in the basic synaptic transmission. Since PPF represents a presynaptic mechanism of synaptic plasticity (Schulz et al. 1994), our results suggest that the improvement of TEN on the basic synaptic transmission seems to be related to a presynaptic mechanism.

TEN increases sEPSCs both in frequency and amplitude

As shown in Fig. 3A, B and D, after recording a stable baseline of sEPSCs for 5-10 min, TEN was applied for 60 s. We observed that TEN increased the frequency of sEPSCs from 100% to 227.56 [+ or -] 33.21% (p < 0.01) and improved their amplitudes from 100% to 202.53 [+ or -] 38.25% (p < 0.01). Additionally, TEN caused a significant right-ward shift in the cumulative distribution of the inter-event intervals of sEPSCs, shown as Fig. 3C. These data suggest that TEN modulated action potential-dependent neurotransmitter release at the Schaffer collateral-CA1 pyramidal neuron synapses, which is consistent with the PPF experiment, and the increase of presynaptic neurotransmitter release induced by TEN is strongly recommended. Considering that the spontaneous release of neurotransmitter is critical for maintaining synaptic strength and controlling spike timing in the brain (Vyleta and Smith 2011), the effectiveness of TEN on mEPSCs was further explored in the next experiment.

TEN increases mEPSCs infrequency but not amplitude

As shown in Fig. 4A, B and D, bath application of 2 [micro]g/ml TEN increased significantly the frequency of mEPSCs occurrence in all neurons recorded from 100 to 201.13 [+ or -] 25.43 (p < 0.01). However, TEN had no effect on the cumulative distribution of the mEPSCs amplitude, exhibiting that there is no shift in the cumulative distribution of the inter-event intervals of mEPSCs, shown as Fig. 4C and D. These findings suggest that TEN also increased action potential-independent neurotransmitter release from the presynaptic terminals of Schaffer collateral-CA1 synapses (Sun and Kapur 2012). Given that spontaneous mEPSCs are believed to be the postsynaptic response to a single spontaneously released synaptic vesicle (Wiegert et al. 2009) and the mEPSCs frequency is related to the modification of presynaptic component, here these results demonstrate that the effect of TEN on the mEPSCs acts only on the presynaptic terminal but not postsynaptic component.

The enhancement on mEPSCs frequency caused by TEN depends on intracellular rather than extracellular [Ca.sup.2+]

Neurotransmitter release from a single vesicle activates a small postsynaptic voltage change and comprises the elementary unit of synaptic communication, and vesicle fusion is triggered by calcium entry through presynaptic VGCCs or may occur spontaneously in the absence of an action potential activity. Consequently, calcium plays a critical role in neurotransmitter release (Wan et al. 2012; Adler et al. 1991). The increase in mEPSCs frequency caused by TEN could be due to [Ca.sup.2+] release from intracellular stores or the entry of extracellular [Ca.sup.2+]. First, we tested whether the [Ca.sup.2+] release from extracellular stores plays a role in the mEPSCs frequency. With incubation in aCSF without calcium, we observed that TEN also increased mEPSCs in frequency but not amplitude, shown as Fig. 5A-D, displaying that extracellular [Ca.sup.2+] does not participate in the enhancement of mEPSCs frequency induced by TEN.

In some ways, the intracellular [Ca.sup.2+] rise underlies spontaneous transmitter release (Rozov et al. 2001; Emptage et al. 2001; Simkus and Stricker 2002). Herein, the release from intracellular calcium stores was blocked by incubating the slice with 50 [micro]M BAPTA-AM, a cell permeable [Ca.sup.2+] chelator. As shown in Fig. 6A-D, under pre-incubating with BAPTA-AM, the mEPSCs frequency displayed no obvious change with TEN as compared to the BAPTA-AM control group (p > 0.05), suggesting that the TEN-induced enhancement on the mEPSCs frequency was blocked by BAPTA-AM. These results indicate that intracellular [Ca.sup.2+] may be involved in the enhancement on mEPSCs frequency induced by TEN.

Discussion

In the present study, we found that bath application of TEN increased the slope of fEPSPs in the hippocampal Schaffer collateral-CA1 pathway of brain slices from rats, indicating that the basic synaptic transmission is improved in hippocampal slices with treatment of TEN. This is consistent with a previous study showing that TEN improves the basic synaptic transmission and synaptic plasticity in the hippocampal slices from mice (Huang et al. 2013). Synaptic transmission is the communication between presynaptic and postsynaptic neurons and the subsequent processing of the signal. These processes are complex and highly regulated, reflecting their importance in normal brain functioning and homeostasis. In order to expand the understanding of the pharmacological role of TEN on regulating the CNS response such as neuroprotection or nootropic effects, therefore, we further examined the potential mechanism of TEN enhancing basic synaptic transmission by using a PPF.

PPF is the well-known phenomenon whereby the fEPSPs response to a second stimulus in enhanced relative to the first if the second stimulus is delivered within a relatively brief period of time after the first, therefore, it always is regarded as a short-term plasticity dependent on presynaptic mechanisms (Craig and Commins 2005; Zucker and Regehr 2002). Additionally, PPF is a dynamic enhancement of transmitter release considered crucial in CNS information processing. The mechanisms of PPF remain controversial and may differ between synapses (Bornschein et al. 2013). Changes in the PPF ratio reflect alterations in synaptic efficacy, which is determined by the probability of neurotransmitter release (Chu et al. 2011). Interestingly, our results demonstrate that the TEN induced enhancement in the fEPSPs slope is associated with a significant decrease in the PPF ratio, suggesting that TEN may be attributable to increasing the amount of presynaptic neurotransmitter release.

In our experiments, we further observed that TEN increases sEPSCs both in frequency and amplitude; however, TEN increases mEPSCs in frequency rather than amplitude. These results show that TEN increases glutamate release including action potential-dependent and action potential-independent at Schaffer collateral-CA1 pyramidal neuron synapses in acute hippocampus slices. The mEPSCs represent the postsynaptic responses to spontaneous release of single neurotransmitter vesicles at functional synapses and thus provide an index of synaptic efficacy and connectivity at a quantal level. According to the quantal hypothesis, the frequency of mEPSCs results from the modification of presynaptic component, and changes in the amplitude of mEPSCs indicate the alteration in postsynaptic component (Basavarajappa et al., 2008; Nelson et al. 2008). Taken together, our data indicate that TEN improved the basic synaptic transmission via a presynaptic mechanism, in which the excitatory neurotransmitter release induced by TEN is strongly recommended.

Furthermore, the present study also shows that TEN induced the presynaptic neurotransmitter release is sensitive to BAPTA- AM but insensitive to the removal of extracellular [Ca.sup.2+], indicating that intracellular [Ca.sup.2+] rather than extracellular [Ca.sup.2+] may be critical for the increase of mEPSCs frequency caused by TEN. Nevertheless, Vyleta and Smith (2011) reported that extracellular [Ca.sup.2+] does not trigger spontaneous glutamate release by simply increasing calcium influx but stimulates the calcium-sensing receptor and thereby promotes resting spontaneous glutamate release. It is still poorly understood whether TEN improves spontaneous neurotransmission release via stimulating the calcium-sensing receptor. Hence, it is necessary for us to further examine this potential mechanism of TEN enhancing the release of presynaptic neurotransmission.

Synaptic transmission is the essential process of brain physiological functions such as the formation on learning and memory. Previous studies have shown that TEN facilitates the induction of long-term potentiation (LTP), a cellular mechanism for learning and memory, and then exhibits a nootropic effect in healthy mice (Huang et al. 2013) or several animal models with cognitive dysfunctions such as memory defect induced by ovariectomy (Cai et al. 2013). Collectively, we speculate that the potential mechanisms of cognitive functions improvement induced by TEN are possibly involving the following processes: increasing the release of presynaptic excitatory neurotransmitter via intracellular calcium, improving the frequency of mEPSCs, potentiating the basic synaptic transmission and the induction of LTP, and then displaying the enhancement of learning and memory.

Additionally, pharmacological studies displayed that TEN exhibits neuroprotective effects. For instance, TEN promotes proliferation and differentiation in hippocampal neural stem cell (Chen et al. 2012). TEN is effective in attenuating [alpha]-synuclein-induced toxicity and [alpha]-synuclein phosphorylation probably via targeting PLK3, suggesting that it could be an efficient therapeutic drug to treat [alpha]-synuclein-related neurodegeneration (Zhou et al. 2013). It remains unknown whether the above mentioned functions are related to the effect of TEN on the basic synaptic transmission. Therefore, the potentially biologic significance of TEN on synaptic transmission as well as pharmacological mechanism remains to be determined in the future.

Conclusion

In summary, the current work demonstrates that TEN displays the facilitation in the basic synaptic transmission by regulating intracellular calcium. We hope that these findings will contribute to explain the mechanism of TEN as a nootropic product or neuroprotective drug in the future.

ARTICLE INFO

Article history:

Received 14 January 2015

Revised 4 May 2015

Accepted 17 May 2015

Abbreviations: aCSF, artificial cerebrospinal fluid; CNS, central nervous system; fEP-SPs, field excitatory postsynaptic potentials; I/O, input/output; LTP, long-term potentiation; mEPSCs, miniature spontaneous excitatory postsynaptic currents; PPF, paired-pulse facilitation; PPR, paired-pulse ratio; PPS, paired-pulse stimulus; sEPSCs, spontaneous excitatory postsynaptic currents; TEN, tenuigenin; VGCCs, voltage-gated [Ca.sup.2+] channels.

Conflict of interest

The authors have no conflict of interest.

Disclosure statement

The authors have nothing to disclose.

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Peng-Jv Wei (1), Li-Hua Yao (1), Dan Dai, Jun-Ni Huang Wen-Xiao Liu, Peng Xiao *, Chu-Hua Li *

School of Life Science, South China Normal University, 55 W Zhongshan Ave., Guangzhou 510631, China

* Corresponding authors. Tel.: +86 20 85211113; fax: +86 20 85215255.

E-mail addresses: xiaopeng@scnu.edu.cn, 365152139@qq.com (P. Xiao), lich@scun.edu.cn (C.-H. Li).

(1) Both authors contributed equally to the paper.

http://dx.doi.org/10.1016/j.phymed.2015.05.008
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Author:Wei, Peng-Jv; Yao, Li-Hua; Dai, Dan; Huang, Jun-Ni; Liu, Wen-Xiao; Xiao, Peng; Li, Chu-Hua
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Aug 15, 2015
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