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Article Cite This: J. Agric. Food Chem. 2017, 65, 10792−10803

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Acute Amino Acid D‑Serine Administration, Similar to Ketamine, Produces Antidepressant-like Effects through Identical Mechanisms I-Hua Wei,† Kuang-Ti Chen,‡ Mang-Hung Tsai,† Ching-Hsiang Wu,⊥ Hsien-Yuan Lane,‡,¶,§ and Chih-Chia Huang*,‡,¶,§ †

Department of Anatomy, ‡Graduate Institute of Biomedical Sciences, and §Department of Psychiatry, China Medical University, 404 Taichung, Taiwan ⊥ Department of Anatomy, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan ¶ Brain Disease Research Center & Department of Psychiatry, China Medical University Hospital, 404 Taichung, Taiwan S Supporting Information *

ABSTRACT: D-Serine is an amino acid and can work as an agonist at the glycine sites of N-methyl-D-aspartate receptor (NMDAR). Interestingly, both types of glutamatergic modulators, NMDAR enhancers and blockers, can improve depression through common targets, namely alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionaic acid receptors (AMPARs) and mammalian target of rapamycin (mTOR). To elucidate the cellular signaling pathway underlying this counterintuitive observation, we activated NMDARs in rats by using D-serine. Saline, ketamine (NMDAR antagonist), and desipramine (tricyclic antidepressant) were used as controls. The antidepressant-like effects of all agents were evaluated using the forced swim test. The activation of the AMPAR−mTOR signaling pathway, release of brain-derived neurotrophic factor (BDNF), and alteration of AMPAR and NMDAR trafficking in the hippocampus of rats were examined. A single high dose of D-serine exerted an antidepressant-like effect that was mediated by rapid AMPAR-induced mTOR signaling pathway and increased BDNF proteins, identical to that of ketamine. Furthermore, in addition to the increased protein kinase A phosphorylation of the AMPAR subunit GluR1 (an indicator of AMPAR insertion in neurons), treatment with individual optimal doses of D-serine and ketamine also increased adaptin β2−NMDAR association (an indicator of the intracellular endocytic machinery and subsequent internalization of NMDARs). Desipramine did not influence these processes. Our study is the first to demonstrate an association between Dserine and ketamine; following adaptative regulation of AMPAR and NMDAR may lead to common changes of them. These findings provide novel targets for safer antidepressant agents with mechanisms similar to those of ketamine. KEYWORDS: amino acid, D-serine, ketamine, depression, NMDA, AMPA, trafficking

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INTRODUCTION Increasing evidence suggests that the glutamatergic system plays a key role in the pathophysiology of psychiatric disorders including depression and schizophrenia.1−6 Consequently, focusing on the glutamatergic system is a new target for treating depression and schizophrenia. For example, the noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine at subanesthetic doses has been reported to cause mood enhancement in healthy individuals7 and rapidly ameliorate depressive symptoms in depressed patients.8,9 Subsequently, other drugs that antagonize NMDARs, such as CGP39551, CGP37849, AP7, and MK-801, also have antidepressant-like actions in preclinical studies.10 Furthermore, the rapid alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated activated mammalian target of rapamycin (mTOR) signaling pathway has been found to be a key mechanism underlying the fast-acting antidepressant effects of NMDAR antagonist ketamine.11,12 In addition, NMDAR antagonists such as ketamine or phencyclidine have been reported to transiently induce schizophrenia-like symptoms.7,13−15 On the basis of the prediction that the enhancement of NMDA function will improve the pathological state induced by NMDAR antagonists, the administration of several amino acids, such as glycine, D-serine (NMDAR © 2017 American Chemical Society

coagonist) or sarcosine (glycine transporter 1 inhibitor), which activate NMDAR, can alleviate psychotic symptoms in patients with schizophrenia.16−19 NMDAR blockers and enhancers are thought to exhibit opposite effects. Paradoxically, preclinical and clinical studies have also found that the directly or indirectly enhanced NMDAR-mediated transmission by using NMDAR modulators, such as D-cycloserine (DCS), GLYX-13, sarcosine, SSR504734, D-serine, benzoate, and N,Ndimethylglycine, has antidepressant effects.20−27 Notably, the antidepressant-like actions of sarcosine, an NMDAR coagonist28 and a competitive GlyT1 inhibitor,29 are exerted through the activated AMPAR−mTOR signaling pathway,30 similar to those of ketamine, an NMDAR antagonist. In addition, a recent study also indicated that the baseline plasma D-serine level can be used to predict an antidepressant response to ketamine in patients with treatment-resistant depression.31,32 The reason that both NMDAR blockers and enhancers alleviate the depressive symptoms of through common targets remains unclear. Comparing NMDAR enhancers and blockers is Received: Revised: Accepted: Published: 10792

September 10, 2017 November 21, 2017 November 22, 2017 November 22, 2017 DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803

Article

Journal of Agricultural and Food Chemistry

Figure 1. Protocol for experiments with D-serine administration and using the inhibitors NBQX and rapamycin. (A) Experimental rats were administered a single intraperitoneal injection with D-serine (560, 1000, and 2000 mg/kg). Saline, ketamine (10 mg/kg), and desipramine (20 mg/ kg) were used as controls. A 15 min preswim exposure was used at 24 h before the forced swim test (FST) session. The (FST was conducted 30 min after injection. (B) To determine the possibility of false-positive result in FST, we separately assess general locomotor activity in a elevated plus maze test (EPM), the rats were administered saline, D-serine (560, 1000, or 2000 mg/kg), ketamine (10 mg/kg), or desipramine (20 mg/kg), once during the experiment. Thirty minuets later, EPM was conducted. Then the rats were sacrificed immediately and rapidly decapitated for biochemical analysis. For acute D-serine treatment with or without inhibitors of AMPAR or mTOR, intraperitoneally pretreratment with NBQX at 10 mg/kg (a AMPA inhibitor) or rapamycin at 20 mg/kg (an mTOR pathway inhibitor) was applied. (C) Rats were treated with either NBQX rapamycin administered 30 min before intraperitoneal D-serine at 1000 mg/kg treatment, and immobility in the FST was determined 30 min after the last injection. Experimental rats were administered saline, NBQX, rapamycin, or D-serine at the doses indicated, and immobility in the FST was determined 30 min after the last injection. A separate study was conducted for biochemical analysis. (D) Rats were administered saline, NBQX, rapamycin, or D-serine at the doses indicated and were sacrificed and then rapidly decapitated 30 min to remove hippocampus after last injection. (E) To investigate the possibility of toxicity, rats were injected with saline or D-serine at the dose indicated and were killed to remove plasma, liver, kidney, hippocampus, and cortex.

The antidepressant action of some NMDAR enhancers, such as DCS or GLYX-13, may result from their potentially antagonist properties at high doses, which is consistent with the action of antagonists, such as ketamine.33,34 D-Serine is a nonessential amino acid involved in glia-synapse interactions that has unique neurotransmitter characteristics.35 Unlike DCS, D-serine is a selective and potent coagonist at the glycine site on

essential for elucidating the cellular signaling mechanism underlying this counterintuitive observation, and the comparison may provide insights into the development of antidepressants. However, until now, the effects of NMDAR enhancers are not as well investigated as those of NMDAR blockers. 10793

DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803

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Journal of Agricultural and Food Chemistry

Figure 2. Percentage of immobility duration in forced swim test (FST) and representative Western blots of rats after acute treatment with saline, ketamine (10 mg/kg), desipramine (20 mg/kg), or D-serine (560, 1000, and 2000 mg/kg). (A) Dose-dependent effect of D-serine on reduced immobility duration was observed. The rats that received a single injection of D-serine at 1000 mg/kg and 2000 mg/kg, ketamine at 10 mg/kg, and desipramine at 20 mg/kg exhibited a significantly reduced immobility duration in the FST [main effect: F (5,54) = 8.663, p < 0.001; n = 10 per group]. (B) Representative Western blots revealed a notably increase of pmTOR, pAkt, and pERK in the hippocampus of rat after treatment with ketamine (10 mg/kg) and acute treatment with D-serine in a dose-dependent manner. (C) Densitometric analysis of pmTOR, pAkt, pERK, and BDNF protein (normalized to β-actin) in the hippocampus after treatments verified the increased immunoreaction of pmTOR, pAkt, pERK, and BDNF protein in each experimental group [main effect: mTOR, F (5,18) = 11.751, p < 0.001; pAkt, F (5,18) = 20.022, p < 0.001; pERK, F (5,18) = 44.878, p < 0.001; BDNF, F (5,18) = 57.893, p < 0.001; n = 4 per group; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 compared with the saline-treated group with the Tukey posthoc analysis]. Values are expressed as mean ± s.e.m.

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NMDAR and coactivates the receptor along with glutamate, which does not act as an antagonist at high doses.36−38 This study investigated the acute effect of D-serine on immobility during the forced swim test (FST) for assessing the potential antidepressant response and activation of the mTOR signaling pathway and release of BDNF. Saline, ketamine (NMDAR antagonist), and desipramine (tricyclic antidepressant) were used as controls. We also examined whether the antidepressantlike effects of D-serine are mediated through the AMPAR− mTOR signal pathway. In addition, our previous study found that sarcosine increased AMPAR membrane insertion, leading to a hypothesis that sarcosine facilitates AMPAR insertion, amplifies the ratio of AMPAR/NMDAR in the postsynaptic membrane, and finally activates the mTOR signaling pathway.30 These effects are identical to those of ketamine. The activation of AMPAR is dependent on NMDAR and vice versa.39 Therefore, in addition to the investigation of the AMPAR insertion, this study also examined the effects of D-serine, ketamine, and desipramine on the NMDAR trafficking to further disclosure why NMDAR enhancers and blockers have the same antidepressant properties.

MATERIALS AND METHODS

Rats and Experimental Design. Male Wistar male rats aged 6−8 weeks old, weighing 250−350 g, were used in this study. The experimental rats were supplied food and water ad libitum. All animal use and procedures conformed to the guide for the care and use of laboratory animals and were approved by the Institutional Animal Care and Use Committee of China Medical University, Taiwan (permit No. 104−263). We dissolved D-serine (Sigma, St. Louis, MO, USA), ketamine (Pfizer, New Taipei City, Taiwan), desipramine (Sigma, St. Louis, MO, USA), NBQX (Tocris, Bristol, UK), and rapamycin (Toku-E, Bellingham, WA, USA) in saline, and all drugs were intraperitoneally injected. Experimental rats were treated with either saline or D-serine at different doses (560, 1000, and 2000 mg/kg) randomly. Additionally, the NMDA antagonist ketamine (10 mg/kg)40 and the tricyclic antidepressant desipramine (20 mg/kg)41,42 were used as positive controls. These rats were first subjected to a 15 min preswim 24 h before the FST (Figure 1A). The next day, after 30 min of administration, the FST was conducted. Each group comprised 10 rats. In another study, the rats were intraperitoneally injected with saline, Dserine, ketamine, and desipramine,43 and at 30 min later, rats were screened in the elevated plus maze test (EPM) to assess the general locomotor activity (Figure 1B). Each experimental group consisted of 8−11 rats. After the EPM test, four rats per group were sacrificed immediately to remove hippocampus for further biochemical analysis. 10794

DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803

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Journal of Agricultural and Food Chemistry

Figure 3. Percentage of immobility duration in forced swim test (FST) and representative Western blots of the rat hippocampal slices after acute intraperitoneal administration of D-serine at 1000 mg/kg and intraperitoneal pretreatment with NBQX at 10 mg/kg or rapamycin at 20 mg/kg. (A) Note that pretreatment of rats with NBQX at 10 mg/kg completely blocks the antidepressant-like effect of D-serine on decreased immobility. Similarly, pretreatment with rapamycin (20 mg/kg) also attenuated the decreased immobility elicited by D-serine in the FST [main effect: F (3,36) = 5.346; p < 0.01, n = 10 per group]. (B) Representative Western blots revealed a notable increase of pmTOR, pAkt, pERK, and BDNF protein in the rat hippocampal slices after acute D-serine treatment. Notably, when rats were intraperitoneal preadministrated with NBQX, the increases of pmTOR, pAkt, ERK, and BDNF protein resulting from acute D-serine treatment is abolished [main effect: mTOR, F (3,12) = 20.484, p < 0.001; pAkt, F (3,12) = 31.754, p < 0.001; pERK, F (3,12) = 33.868, p < 0.001; BDNF, F (3,12) = 6.242, p < 0.01; n = 4 per group]. The increased expression of pmTOR and release of BDNF resulting from acute D-serine treatment is blocked on pretreatment with rapamycin, but the increases of pAkt and pERK resulting from acute D-serine treatment are not reversed (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 compared with the saline+salinetreated group; #p < 0.05, ##p < 0.01, ###p < 0.001 compared with the saline+D-serine-treated group with the Tukey posthoc analysis). Values are expressed as mean ± s.e.m. intraperitoneally injected 30 min before treatment with D-serine at 1000 mg/kg or saline. The treated-rats were assessed in the FST 30 min later. In a separate study, 16 rats were divided to four groups randomly, with four rats for each group (Figure 1D). Thirty minutes before intraperitoneally administration of D-serine at 1000 mg/kg, saline, NBQX at 10 mg/kg, or rapamycin at 20 mg/kg was

In addition, the 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX, a AMPAR inhibitor) or rapamycin (an mTOR pathway inhibitor) was used to validate whether D-serine might provide antidepressant-like actions mediating by these signaling pathways directly (Figure 1C). Each group comprised 10 experimental rats. Saline, NBQX at 10 mg/kg,12 or rapamycin at 20 mg/kg44 was 10795

DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803

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Journal of Agricultural and Food Chemistry

Figure 4. Representative Western blots of (A) pGluR1ser845 and (B) immunoexpression of NMDAR2A/B and adaptin β2 from the rat hippocampal slices intraperitoneally treated with saline, D-serine (560, 1000, and 2000 mg/kg), ketamine (10 mg/kg), or desipramine (20 mg/kg) and (C,D) after D-serine at 1000 mg/kg intraperitoneally preadministration with NBQX at 10 mg/kg or rapamycin at 20 mg/kg. Acute D-serine treatment increased (A) the expression of pGluR1ser845 and (B) the association of NMDAR2A/B and adaptin β2 significantly in a dose-dependent manner [main effect: F (5,18) = 16.783, p < 0.001; F (5,18) = 13.484, p < 0.001; respectively]. Ketamine (10 mg/kg) also significantly enhanced phosphorylated GluR1ser845 and AP2−NMDAR association, which was not observed in desipramine-treated (20 mg/kg) rats (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 compared with saline-treated group with the Tukey posthoc analysis; n = 4 per group). When rats were pretreated with NBQX, the increase of pGluR1ser845 caused by acute D-serine treatment was reversed (c) [main effect: F (3,12) = 10.796, p = 0.001]. However, the effects do not diminished by rapamycin pretreatment (C). Increase of the association of adaptin β2-NMDAR resulting from acute D-serine treatment was not abolished when rats were pretreated with NBQX or rapamycin (D) [main effect: F (3,12) = 25.300, ∗p < 0.001, ∗∗p < 0.01, ∗∗∗p < 0.001 compared with saline+saline-treated group; ##p < 0.01 compared with saline+D-serine-treated group with the Tukey posthoc analysis; n = 4 per group]. Values are expressed as mean ± s.e.m. intraperitoneally injected. Thirty minutes after the final administration, these experimental rats were sacrificed to remove hippocampus for biochemical analysis. Besides, in this study, the assessment of the toxicity of D-serine was ̈ rats were divided to four groups with also carried out. Sixteen naive four rats for each group randomly (Figure 1E). The saline or D-serine at different doses (560, 1000, and 2000 mg/kg) was intraperitoneally injected. Thirty minutes following the injection, these experimental rats were killed to remove liver, kidney, hippocampus, and cortex and collect plasma from blood for toxicity assessment. FST and EPM Test. The FST and EPM procedures were performed as previously described.30 On the EPM, the total number of closed arm entries and distances traveled were quantitatively measured as a index of general locomotor activity to assess the possibility of false-positive result in the FST.45,46 Western Blot Analysis and Immunoprecipitation of AP2 with NMDARs. The tissue processing and Western blotting were performed as previously described.30,47 The phosphorylated forms of mTOR (pmTOR), Akt (pAkt), extracellular signal-regulated protein kinase (pERK), (mTOR upstream kinases), BDNF protein, and PKA phosphorylation of AMPAR subunit GluR1 were analyzed through

Western blotting. The endocytotic machinery of the NMDARs was analyzed through an immunoprecipitation assay of anti-AP2 and NMDARs, which was adapted from a previous report.48 Evaluation of Liver and Kidney Function. Using commercial kits (Wako, Osaka, Japan), we measured the alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine levels in the plasma to detect liver and kidney function. In Situ Apoptosis Assay and Histological Analysis of Liver, Kidney, and Brain Tissues. In situ apoptosis and histology were determined by fixing the liver, kidney, and brain in buffered formalin, processing, embedding in paraffin, and then staining with hematoxylin and eosin (HE). Stained slides were analyzed and captured on a Zeiss microscope (Zeiss, Oberkochen, Germany). Statistical Analysis. All data were reported as mean ± s.e.m. The Kolmogorov−Smirnov test and Levenes’s test were applied to test the assumption of normality and homogeneity of variance, respectively. The behavioral experiment data showed a parametric distribution. In addition, biochemical experiment data about the expression of Western blot analysis and immunoprecipitation were quantified as fold changes in each band relative to saline-treated group, which were 10796

DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803

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Journal of Agricultural and Food Chemistry

Figure 5. Effect of D-serine at different doses (560, 1000, and 2000 mg/kg) on serum marker enzymes such as (A) aspartate aminotransferase (AST), (B) alanine aminotransferase (ALT), (C) blood urea nitrogen (BUN), and (D) creatinine [main effect: AST, F (3,12) = 2.235, p > 0.05; AST, F (3,12) = 0.295, p > 0.05; BUN, F (3,12) = 1.102, p > 0.05; creatinine F (3,12) = 2.000, p > 0.05; n = 4 per group]. Values are expressed as mean ± s.e.m. taken in triplicate readings. The level of saline-treated group set at 100%. The parameters of biochemical data were tested concerning normality (Kolmogorov−Smirnov test), and the data showed a parametric distribution. Finally, data of the behavioral and biochemical experiments were evaluated using the one-way analysis of variance followed by Tukey posthoc test (SPSS 12.0) for multiple comparisons. All statistical tests were two-tailed. A p-value of less than 0.05 was regarded statistically significant. Each behavioral experimental group consisted of 8−11 rats. Each biochemical experimental group consisted of four rats.

Akt, ERK, and BNDF proteins were measured following Dserine treatment. The rats treated with D-serine at high doses (1000 mg/kg and 2000 mg/kg) exhibited significant increases of immunoreactivity of pmTOR, pAkt, and pERK (Figure 2B). The levels of total mTOR, Akt, and ERK remained unaltered. The increased pmTOR activity of the D-serine-treated rats was also confirmed in statistic analysis (Figure 2C). The similar trends were also noted in both mTOR upstream regulators (pAkt and pERK) (Figure 2C). Furthermore, compared with the saline-treated group, the rats in the D-serine group treated with all doses 560, 1000, and 2000 mg/kg exhibited a significant increase in the BDNF level (Figure 2C). Similar effects of increased activation of mTOR signaling and BDNF protein level were observed in rats treated with the NMDAR antagonist ketamine at a subanesthetic dose but not in desipramine-treated ones. Role of AMPAR and mTOR Signaling on D-SerineInduced Antidepressant-like Actions. To investigate the involvement of AMPAR and mTOR signaling on the D-serineinduced antidepressant-like actions, NBQX (10 mg/kg), an AMPAR antagonist, and rapamycin (20 mg/kg), an mTOR inhibitor, were applied. Figure 3A shows the NBQX administration 30 min before D-serine treatment abolished the D-serine-induced antidepressant-like actions of decreased immobility. Similarly, rapamycin completely reversed the reduced immobility in the FST (Figure 3A). These findings indicate that the antidepressant-like properties of D-serine required the activations of mTOR signaling and AMPAR.

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RESULTS AND DISCUSSION Acute Antidepressant Effects of D-Serine. A dosedependent reduction in the immobility time was observed when rats were injected with D-serine during the FST (Figure 2A). Compared with the saline-treated control rats, the rats treated with D-serine at high doses (1000 mg/kg and 2000 mg/ kg) showed a significantly reduced immobility time. Ketamine and desipramine also significantly reduced immobility. Furthermore, to examine whether these compounds yielded a pseudopositive effect during the FST, we measured the total number of closed arm entries and distances traveled in the EPM as indicators of general locomotor activity.45,46 At the doses tested, neither D-serine nor ketamine and desipramine increased locomotor activity; however, a high dose (2000 mg/ kg) of D-serine significantly reduced the general activity. To evaluate whether the antidepressant-like effects is accompanied by an increase in the activated mTOR signaling and BDNF release, the levels of the phosphorylation of mTOR, 10797

DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803

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Journal of Agricultural and Food Chemistry

Figure 6. (a−h) Bright-field (HE) and (i−p) fluorescence photomicrographs in the (A) liver, (B) kidney, (C) hippocampus, and (D) cortex of rats being treated with (a, e, i, m) normal saline, (b, f, j, n) D-serine 560 mg/kg, (c, g, k, o) 1000 mg/kg, and (d, h, l, p) 2000 mg/kg. After staining with HE, histopathological examinations were performed under light microscopy at 100× (a−d, scale bar, 100 mm) and 200× (e−p, Scale bar, 50 mm) magnifications. At higher magnification, liver slices demonstrated well-organized hepatocytes radiating from the central vein (arrows in A) with intact liver plates and portal triads were observed in normal saline, D-serine 560, 1000, and 2000 mg/kg groups (A, e−h). Examination of kidney sections in all groups revealed that the kidney tissues retained its normal architecture in glomeruli (arrows in B) and surrounding with proximal and distal convoluted tubules convoluted tubules (B, a−h). HE staining of hippocampal neurons (arrows in C) arranged closely, neuronal structure is complete and clear. There are no degeneration and atrophy changes in pathological patterns between control and D-serine treated rats (C, a−h). Photomicrographs of the Inner pyramidal layer of the cerebral cortex in Control or D-serine treated groups (D, a−h) exhibiting a normal morphology, the organisational structure in the pyramidal cells (arrows in D) were no morphologically altered. In rats treated with normal saline, D560, D1000, D2000 mg/kg, no TUNEL-positive cells were revealed in the tissues of liver, kidney, hippocampus, and cortex (A−D, m−p). All cells were morphologically determined using colocalized DAPI staining (A−D, i−l).

Role of Glutamatergic System on D-Serine-Induced Antidepressant-like Actions and BDNF Release. We further studied whether the activity of AMPAR-mTOR signaling pathway and release of BDNF caused by D-serine treatment can be affected by pretreatment with NBQX or rapamycin. Similarly, acute D-serine treatment at 1000 mg/kg increased the immunoreactivity of pmTOR, pAkt, pERK, and BDNF significantly (Figure 3B). There were no changes for total mTOR, Akt, and ERK levels. Pretreatment with NBQX abolished the D-serine-induced increase in the immunoreactivity of pmTOR, pAkt, pERK, and BDNF proteins (Figure 3B). The increases of immunoreactivity of pmTOR and BDNF following D-serine treatment were completely reversed by rapamycin administration (Figure 3B), but increased pAkt and pERK levels induced by D-serine were not abolished (Figure 3B). These results suggest that D-serine stimulates the mTOR signaling pathway and BDNF release, which is dependent on AMPAR activation. Alteration of AMPAR Membrane Insertion and NMDAR Membrane Internalization Following Acute DSerine or Ketamine Treatment. We determined whether Dserine regulates the phosphorylation of AMPAR subunit GluR1ser845 and coprecipitation of NMDARs together with AP2 after an acute in vivo treatment in rats to investigate the

influence of D-serine on the AMPAR membrane insertion and NMDAR membrane internalization.49−53 As shown in Figure 4A and B, a dose-dependent increase in the phosphorylation of hippocampal GluR1ser845 and the level of NMDARs precipitating tightly with AP2 were observed in the rats treated with D-serine. When compared with the saline-treated controls, D-serine at high doses significantly increased the phosphorylation of GluR1ser845 in a dose-dependent manner (Figure 4A) and the association of AP2 and NMDARs (Figure 4B). Furthermore, ketamine at a subanesthetic dose as a positive control also significantly enhanced the phosphorylated GluR1ser845 and AP2−NMDAR association, which was not observed in desipramine-treated rats (Figure 4A,B). These results are significantly consistent with those of mTOR activation and BDNF release. Pretreatment with NBQX abolished the D-serine-induced increased activity of pGluR1ser845. However, rapamycin pretreatment did not reverse the D-serine-induced increase (Figure 4C). Pretreatment with NBQX or rapamycin did not block the D-serine-induced increase in the AP2−NMDAR association (Figure 4D). The total GluR1 and AP2 levels remained unchanged (Figure 4). These data indicated that Dserine in a dose-dependent manner and ketamine at a subanesthetic dose enhanced AMPAR membrane insertion 10798

DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803

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these effects. These findings are the first to demonstrate an association between D-serine and ketamine; following adaptative regulation of AMPAR and NMDAR at their individual optimal doses may lead to common changes of them. We observed that high doses of D-serine reduced immobility during the FST without an increase in general activity, thus demonstrating its antidepressant-like effect. These results are consistent with the reported antidepressant-like responses of other NMDAR enhancers.20−22,30,54 Moreover, a single injection of D-serine activated the mTOR signaling pathway rapidly in a dose-dependent manner. Pretreatment with mTOR or AMPAR inhibitor significantly blocked the antidepressantlike effects in FST and the increases levels of activated form of mTOR signaling pathways proteins caused by D-serine. The present evidence clearly confirmed that the activated AMPA− mTOR signaling pathway is necessary for the antidepressantlike actions of the NMDAR coagonist D-serine and, essentially, identical mechanisms underlie the antidepressant-like effects of ketamine at a subanesthetic dose.11 In addition to activation of mTOR, BDNF release also involves in the fast-acting antidepressant-like effect of ketamine.55 Therefore, we evaluated whether D-serine altered the BDNF level. As expected, ketamine instantly increased the BDNF protein level. Interestingly, the rats treated acutely with a single dose of D-serine, similar to ketamine, produced an identical effect in a dose-dependent manner. The similar effects of D-serine and ketamine extend to the BDNF level. In this study, both pretreatment with NBQX and rapamycin reversed the D-serineinduced increase in the hippocampal BDNF protein level, thereby suggesting that mTOR activation leads to an increased BDNF release. However, this is different; previous studies have indicated that the ketamine-induced mTOR activation lies downstream from increased BDNF mediated by AMPAR.56 Although the exact mechanism remains uncertain, the activated BDNF/mTOR signaling pathway also increased the number of cells in the hippocampal dentate gyrus and established a positive feedback loop of BDNF productions following the activation of mTOR.57,58 Rapamycin may deactivate the positive feedback loop, which in turn reduced the upstream BDNF. Furthermore, to study the effects of D-serine on both AMPAR and NMDAR trafficking, here, we measured the PKA site of AMPAR subunit GluR1 phosphorylation, which is an indicator for insertion of GluR1 membrane in neurons, and the AP2−NMDAR association, which is an indicator of NMDAR membrane internalization. The results demonstrated that Dserine rapidly increases AMPAR membrane insertion in dosedependent manner. Moreover, our study is the first to demonstrate that a single dose of D-serine treatment caused the recruitment of the endocytic machinery to the NMDARs in vivo, thus leading to NMDAR internalization in a dosedependent manner. These findings are consistent with those of a previous in vitro study, which showed that NMDAR internalization can be primed by an increase in glycine or Dserine for subsequent internalization on stimulation of glutamate and glycine sites.48 Notably, we observed that ketamine also exhibited increased effects on AMPAR membrane insertion and recruitment of the endocytic machinery to the NMDARs, which were identical to the change observed following the administration of D-serine at high dose. Thus, the enhancement of AMPAR insertion and NMDAR internalization represent common features of the

and NMDAR membrane internalization. The AMPAR activation is required for D-serine-induced AMPAR membrane insertion but not for the NMDAR membrane internalization. Effects of D-Serine Exposure on Levels of ALT, AST, BUN, and Creatinine. ALT and AST are indices of cellular necrosis and tissue damage in liver. The rats treated with Dserine at 560 mg/kg, 1000 mg/kg, and 2000 mg/kg showed no significant difference in mean values of the serum ALT (Figure 5A) and AST (Figure 5B) in comparison to those of salinetreated rats. In addition, BUN and creatinine are indices of cellular necrosis and tissue damage in kidney. The rats treated with D-serine at 560 mg/kg, 1000 mg/kg, and 2000 mg/kg showed no significant difference in mean values of the serum BUN (Figure 5C) and creatinine (Figure 5D) compared to saline-treated rats. Histological Analysis and TUNEL Staining of Liver, Kidney, Hippocampus, and Cortex. Histological of HE staining and apoptosis TUNEL assay were performed to observe the histological change and dying cells of acute administration of D-serine at 560 mg/kg, 1000 mg/kg, and 2000 mg/kg on liver (Figure 6A), kidney (Figure 6B), hippocampus (Figure 6C), and cortex (Figure 6D) in experimental rats. Analysis of HE -stained liver slices of rats treated with normal saline, D-serine 560 mg/kg, 1000 mg/kg, and 2000 mg/kg (Figure 6A) showed a general preservation of liver histoarchitecture, hepatocytes with a normal cytoplasmic eosinophilic aspect, and one or two nuclei with loose chromatin and evident nucleolus. No other visual signs of hepatotoxicity being observed after D-serine 560 mg/kg, 1000 mg/kg, and 2000 mg/kg treatment. In kidney tissues, no histological architecture change was observed after administration of normal saline and D-serine (560 mg/kg, 1000 mg/kg, and 2000 mg/kg) (Figure 6B). The well-designated glomeruli have numerous capillary loops with surrounding proximal and distal convoluted tubules in the cortical region of kidney in control or different doses of Dserine treated groups (Figure 6B). HE staining of hippocampal tissues in normal saline, D-serine 560 mg/kg, 1000 mg/kg, and 2000 mg/kg-treated rats showed normal histological features (Figure 6C). The hippocampal pyramidal neurons are regularly arranged, the nucleus is big and round, nucleoli are clear. There were no significant atrophy and histopathological changes in the hippocampal region of rats treated with normal saline or D-serine (Figure 6C). The results of HE staining showed a normal distribution of neurons in the cerebral cortex of the normal saline group. The rounded nuclei, small neurites, pyramidal cells with elliptic neuronal bodies, well-defined nucleoli, and a basophilic cytoplasm were observed. Compared with the saline-treated rats group, there were no morphological changes in the D-serine treated groups (Figure 6D). There were no TUNEL-positive cells were detected in the tissues of all groups (Figure 6). The present study provides convincing evidence that a single injection of amino acid D-serine, an NMDAR coagonist, at high doses provides antidepressant-like effects during the FST, and elicits its action, at the molecular level, in a manner identical to that of ketamine, an NMDAR antagonist, at subanesthetic dose. In addition, similar to ketamine, D-serine at high doses causes the rapid AMPAR-mediated mTOR signaling pathway activation. Interestingly, both of them increase the PKA phosphorylation of AMPAR subunit GluR1 and AP2− NMDAR association. Notably, acute treatment with the conventional antidepressant, desipramine, did not exhibit 10799

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Figure 7. Proposed cellular signaling pathways underlying the common antidepressant-like properties for both NMDAR coagonist D-serine and NMDAR antagonist ketamine. The activation of synaptic NMDARs by the coagonist D-serine at high doses induces AMPAR insertion into the postsynaptic membrane and NMDAR internalization at postsynaptic sites, which amplify the postsynaptic AMPAR/NMDAR ratio, leading to enhanced glutamatergic AMPAR to NMDAR stimulation. The increased glutamatergic throughput of AMPARs caused the activation of mTOR and release of BDNF. Ultimately, D-serine exhibits antidepressant-like actions. Meanwhile, ketamine at subanesthetic dose can induce extracellular glutamate. Increased glutamate release activates AMPARs and stimulates mGluR, resulting in NMDAR internalization. This will also increase AMPAR throughput, thereby contributing to an activated mTOR signaling pathway that results in antidepressant action. By contrast, a high anesthetic dose of ketamine reduces glutamate levels and may upregulate NMDARs, which may also explain why an anesthetic dose of ketamine cannot produce an antidepressant effect.

of metabotropic glutamate receptors (mGluR) with glutamate can activate NMDAR internalization.52,60 Therefore, ketamine at a low subanesthetic dose may increase the extracellular glutamate levels, followed by the mGluR stimulation active NMDAR internalization. The consequence results from a combined effect of AMPAR and NMDAR adaptative trafficking caused by NMDAR coagonist D-serine and NMDAR antagonist ketamine at their respective optimal doses, which in turn lead to identical changes at the behavioral and molecular levels. Ketamine blocks NMDAR, whereas D-serine acts as an NMDAR coagonist. In an intuitive manner, the effects of Dserine and ketamine can be easily considered to be the opposite. However, acutely increased levels of NMDAR coagonist D-serine can lead to an adaptive downregulation and desensitization of postsynaptic NMDARs.48 Moreover, repeated administration of NMDAR antagonist ketamine at high doses upregulates the NMDARs.61−63 On the basis of these observations, negative feedback for the regulation of NMDAR homeostasis occurs in response to glutamatergic NMDAR modulators including both enhancers and blockers. Hence, the combined effect of adaptive changes in AMPAR and NMDAR numbers or sensitivity following ketamine or D-serine administration at their individual optimal doses may provide a final common AMPAR/NMDAR ratio in the postsynaptic membrane, thereby yielding convergent outcomes in their downstream mTOR signal pathway for antidepressant action (Figure 7). Such mechanisms may apply broadly to the absence of the effect of ketamine at high anesthetic dose. The current study and other works on the mechanisms underlying the

treatment of both the NMDAR coagonist D-serine and antagonist ketamine at their optimal doses. The current findings clearly demonstrate that the activated AMPAR-mTOR signaling pathway is required for the behavioral actions of D-serine in the FST, importantly, showing a convergence with the mechanisms underlying the action of ketamine. When assessing the AMPAR and NMDAR trafficking, we observed that the NMDAR coagonist D-serine enhanced AMPAR insertion in a dose-dependent manner and theoretically caused the subsequent upregulation of AMPARs. Furthermore, in this in vivo study, we demonstrated for the first time that acute administration of D-serine could have led to the recruitment of AP2 for priming the internalization of NMDAR in a dose-dependent manner, consistent with a previous in vitro study48 and theoretically have caused the subsequent downregulation of NMDARs. Following D-serine administration, particularly at high doses, the combined effect of AMPR insertion and NMDAR internalization resulted in the high AMPAR:NMDAR ratio in the postsynaptic membrane may favor AMPAR throughput and thereby contribute to an activated mTOR signaling pathway, which in turn lead to antidepressant action. Notably, we also found that ketamine at subanesthetic doses acted as a positive control increased AMPAR insertion and NMDAR internalization, similar to the action of D-serine at higher doses. Ketamine-primed NMDAR internalization is not entirely unexpected because ketamine not only acts as an antagonist of NMDAR, but also increases extracellular glutamate levels at low subanesthetic doses, whereas anesthetic doses reduce these levels.59 The stimulation 10800

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antidepressant action of ketamine are complementary and not contradictory to each other. Our data indicated a novel mechanism in which the feedback induced by glutamatergic modulators at their individual optimal doses results in increased NMDAR internalization and AMPAR insertion finally, this combined effect lead to antidepressant action. Clearly, additional studies are necessary to causally link the action of ketamine at wide-range doses to the potential change in AMPAR and NMDAR trafficking. Behavior analysis using FST revealed that D-serine at high doses, ketamine, and desipramine exerted antidepressant-like effects. However, only D-serine and ketamine, but not desipramine, increased activation of the mTOR signaling and release of BDNF following a single dose. The rapid induction of mTOR signaling and the increased BDNF level mediate the fast-acting antidepressant effects of ketamine, which may represent a mechanism common to other putative rapid antidepressants.11,55,64 By contrast, traditional antidepressants do not rapidly increase the mTOR signaling and BDNF levels, elevated BDNF and mTOR levels are only evident following chronic treatment, which corresponds to the time course of the clinical effect.11,55,65 Therefore, the rapidly increased mTOR signaling and BNDF level is proposed to be crucial for the development of antidepressants with fast-acting onset. Our results from this series of experiments suggest that D-serine at high dose might have rapid antidepressant effect in human, similar to that of ketamine.11 In this preclinical study, these rats treated with D-serine at 560 to 2000 mg/kg once did not have histological change and did not have impaired liver and kidney function. A clinical study also reports doses of D-serine ranging from 30 to 120 mg/kg/d following a 4-week adjunctive treatment were well tolerated in patients with schizophrenia; however, one patient did show a nephrotoxic-like pattern at 120 mg/kg/day.66 The rats treated with D-serine at 1000 mg/kg and 2000 mg/kg showed antidepressant-like responses, the equivalent doses in humans would be predicted to be 135.7 mg/kg and 271.4 mg/kg, respectively.67 Currently, clinical application with D-serine at high dose remains lacking, but present results are encouraging of further study of higher-dose D-serine. Although much work is required for clarifying the actual therapeutic potential of NMDAR coagonist, taken together, the use of NMDAR coagonists may be a novel therapeutic strategy to develop fast-acting antidepressants. In conclusion, the amino acid D-serine has been demonstrated to play crucial roles in brain development, synaptic plasticity, depression, and cognition.68−71 Our results provide direct evidence that the NMDAR coagonist D-serine at high dose exerts antidepressant-like effect via the rapidly activated AMPA−mTOR signaling pathway, which is identical to the effects of ketamine at subanesthetic doses. Not just simple NMDAR inhibition or enhanced AMPAR throughput, we hypothesize that the combined effect of adaptative regulation in AMPAR and NMDAR induced by NMDAR coagonist D-serine or antagonist ketamine treatment may result in a common change to possess identical antidepressant-like action. The results provide a novel opportunity for investigating the mechanisms that mediate rapid antidepressant effects. Furthermore, our results may provide new insights into the pathogenesis of depression. Most importantly, our behavioral and biochemical findings raise the possibility that D-serine has the potential of being highly efficacious and safer to treat depression, with mechanisms similar to those of ketamine.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.7b04217. Composition of materials and methods (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 886-422052121 ext 1015. Fax: 886-4-22361230. ORCID

Chih-Chia Huang: 0000-0001-8703-1878 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Ministry of Science and Technology, Taiwan (MOST 105-2314-B-039-027, MOST 105-2320-B-039-013-MY3, and MOST 106−2314 - B - 039− 029 - MY3) and China Medical University Hospital, Taiwan (DMR-105-075, DMR-106-096).

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ABBREVIATIONS USED NMDAR, N-methyl-D-aspartate receptor,; AMPAR, alphaamino-3-hydroxy-5-methyl-4-isoxazolepropionaic acid receptors,; mTOR, mammalian target of rapamycin; ERK, extracellular signal-regulated protein kinase; GluR1ser845, AMPA GluR1 serine845; BDNF, brain-derived neurotrophic factor; pmTOR, phospho-mTOR; pERK, phospho-extracellular signal-regulated protein kinase; pAkt, phospho-Akt; pGluR1ser845, phospho-AMPA GluR1 serine845; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; HE, hematoxylin−eosin; GlyT1, glycine transporter 1; DCS, D-cycloserine; FST, forced swim test; EPM, elevated plus maze test; mGluR, metabotropic glutamate receptors

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REFERENCES

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DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803

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DOI: 10.1021/acs.jafc.7b04217 J. Agric. Food Chem. 2017, 65, 10792−10803