Abstract
Sarcosine, an endogenous amino acid, is a competitive inhibitor of the type I glycine transporter and an N-methyl-D-aspartate receptor (NMDAR) coagonist. Recently, we found that sarcosine, an NMDAR enhancer, can improve depression-related behaviors in rodents and humans. This result differs from previous studies, which have reported antidepressant effects of NMDAR antagonists. The mechanisms underlying the therapeutic response of sarcosine remain unknown. This study examines the role of mammalian target of rapamycin (mTOR) signaling and α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) activation, which are involved in the antidepressant-like effects of several glutamatergic system modulators. The effects of sarcosine in a forced swim test (FST) and the expression levels of phosphorylated mTOR signaling proteins were examined in the absence or presence of mTOR and AMPAR inhibitors. In addition, the influence of sarcosine on AMPAR trafficking was determined by analyzing the phosphorylation of AMPAR subunit GluR1 at the PKA site (often considered an indicator for GluR1 membrane insertion in neurons). A single injection of sarcosine exhibited antidepressant-like effects in rats in the FST and rapidly activated the mTOR signaling pathway, which were significantly blocked by mTOR inhibitor rapamycin or the AMPAR inhibitor 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) pretreatment. Moreover, NBQX pretreatment eliminated the ability of sarcosine to stimulate the phosphorylated mTOR signaling proteins. Furthermore, GluR1 phosphorylation at its PKA site was significantly increased after an acute in vivo sarcosine treatment. The results demonstrated that sarcosine exerts antidepressant-like effects by enhancing AMPAR–mTOR signaling pathway activity and facilitating AMPAR membrane insertion. Highlights – A single injection of sarcosine rapidly exerted antidepressant-like effects with a concomitant increase in the activation of the mammalian target of rapamycin mTOR signaling pathway. – The antidepressant-like effects of sarcosine occur through the activated AMPAR–mTOR signaling pathway. – Sarcosine could enhance AMPAR membrane insertion via an AMPAR throughput.
| Original language | English |
|---|---|
| Article number | 162 |
| Journal | Frontiers in Behavioral Neuroscience |
| Volume | 9 |
| Issue number | JUNE |
| DOIs | |
| Publication status | Published - Jun 18 2015 |
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Keywords
- AMPA
- Depression
- mTOR
- NMDA
- Sarcosine
ASJC Scopus subject areas
- Behavioral Neuroscience
- Cognitive Neuroscience
- Neuropsychology and Physiological Psychology
Cite this
AMPA receptor–mTOR activation is required for the antidepressant-like effects of sarcosine during the forced swim test in rats : Insertion of AMPA receptor may play a role. / Chen, Kuang Ti; Tsai, Mang Hung; Wu, Ching Hsiang; Jou, Ming Jia; Wei, I. Hua; Huang, Chih Chia.
In: Frontiers in Behavioral Neuroscience, Vol. 9, No. JUNE, 162, 18.06.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - AMPA receptor–mTOR activation is required for the antidepressant-like effects of sarcosine during the forced swim test in rats
T2 - Insertion of AMPA receptor may play a role
AU - Chen, Kuang Ti
AU - Tsai, Mang Hung
AU - Wu, Ching Hsiang
AU - Jou, Ming Jia
AU - Wei, I. Hua
AU - Huang, Chih Chia
PY - 2015/6/18
Y1 - 2015/6/18
N2 - Sarcosine, an endogenous amino acid, is a competitive inhibitor of the type I glycine transporter and an N-methyl-D-aspartate receptor (NMDAR) coagonist. Recently, we found that sarcosine, an NMDAR enhancer, can improve depression-related behaviors in rodents and humans. This result differs from previous studies, which have reported antidepressant effects of NMDAR antagonists. The mechanisms underlying the therapeutic response of sarcosine remain unknown. This study examines the role of mammalian target of rapamycin (mTOR) signaling and α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) activation, which are involved in the antidepressant-like effects of several glutamatergic system modulators. The effects of sarcosine in a forced swim test (FST) and the expression levels of phosphorylated mTOR signaling proteins were examined in the absence or presence of mTOR and AMPAR inhibitors. In addition, the influence of sarcosine on AMPAR trafficking was determined by analyzing the phosphorylation of AMPAR subunit GluR1 at the PKA site (often considered an indicator for GluR1 membrane insertion in neurons). A single injection of sarcosine exhibited antidepressant-like effects in rats in the FST and rapidly activated the mTOR signaling pathway, which were significantly blocked by mTOR inhibitor rapamycin or the AMPAR inhibitor 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) pretreatment. Moreover, NBQX pretreatment eliminated the ability of sarcosine to stimulate the phosphorylated mTOR signaling proteins. Furthermore, GluR1 phosphorylation at its PKA site was significantly increased after an acute in vivo sarcosine treatment. The results demonstrated that sarcosine exerts antidepressant-like effects by enhancing AMPAR–mTOR signaling pathway activity and facilitating AMPAR membrane insertion. Highlights – A single injection of sarcosine rapidly exerted antidepressant-like effects with a concomitant increase in the activation of the mammalian target of rapamycin mTOR signaling pathway. – The antidepressant-like effects of sarcosine occur through the activated AMPAR–mTOR signaling pathway. – Sarcosine could enhance AMPAR membrane insertion via an AMPAR throughput.
AB - Sarcosine, an endogenous amino acid, is a competitive inhibitor of the type I glycine transporter and an N-methyl-D-aspartate receptor (NMDAR) coagonist. Recently, we found that sarcosine, an NMDAR enhancer, can improve depression-related behaviors in rodents and humans. This result differs from previous studies, which have reported antidepressant effects of NMDAR antagonists. The mechanisms underlying the therapeutic response of sarcosine remain unknown. This study examines the role of mammalian target of rapamycin (mTOR) signaling and α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) activation, which are involved in the antidepressant-like effects of several glutamatergic system modulators. The effects of sarcosine in a forced swim test (FST) and the expression levels of phosphorylated mTOR signaling proteins were examined in the absence or presence of mTOR and AMPAR inhibitors. In addition, the influence of sarcosine on AMPAR trafficking was determined by analyzing the phosphorylation of AMPAR subunit GluR1 at the PKA site (often considered an indicator for GluR1 membrane insertion in neurons). A single injection of sarcosine exhibited antidepressant-like effects in rats in the FST and rapidly activated the mTOR signaling pathway, which were significantly blocked by mTOR inhibitor rapamycin or the AMPAR inhibitor 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) pretreatment. Moreover, NBQX pretreatment eliminated the ability of sarcosine to stimulate the phosphorylated mTOR signaling proteins. Furthermore, GluR1 phosphorylation at its PKA site was significantly increased after an acute in vivo sarcosine treatment. The results demonstrated that sarcosine exerts antidepressant-like effects by enhancing AMPAR–mTOR signaling pathway activity and facilitating AMPAR membrane insertion. Highlights – A single injection of sarcosine rapidly exerted antidepressant-like effects with a concomitant increase in the activation of the mammalian target of rapamycin mTOR signaling pathway. – The antidepressant-like effects of sarcosine occur through the activated AMPAR–mTOR signaling pathway. – Sarcosine could enhance AMPAR membrane insertion via an AMPAR throughput.
KW - AMPA
KW - Depression
KW - mTOR
KW - NMDA
KW - Sarcosine
UR - http://www.scopus.com/inward/record.url?scp=84933047409&partnerID=8YFLogxK
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U2 - 10.3389/fnbeh.2015.00162
DO - 10.3389/fnbeh.2015.00162
M3 - Article
VL - 9
JO - Frontiers in Behavioral Neuroscience
JF - Frontiers in Behavioral Neuroscience
SN - 1662-5153
IS - JUNE
M1 - 162
ER -