{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T03:04:17Z","timestamp":1772593457365,"version":"3.50.1"},"reference-count":28,"publisher":"IMR Press","issue":"4","license":[{"start":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T00:00:00Z","timestamp":1577664000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Correlations amongst the rat glutamatergic system, glia, and depression, as well as the underlying mechanism of astrocyte impairment, as a trigger of depression, were investigated. Rats were submitted to different durations of chronic unpredictable mild stress to induce depressive-like behavior and evaluated by weight change, sucrose preference test, open field test, and novelty suppressed feeding test. High-performance liquid chromatography was employed to detect glutamate content of hippocampal protein expression during Western blot and immunofluorescence. Results showed that 21-day chronic unpredictable mild stress was sufficient for inducing significant depressive-like behavior (reduced body weight and sucrose preference, increased feeding, and immobility time) in a model of depression. Chronic unpredictable mild stress increased the level of hippocampal glutamate, while intervention caused a considerable rise in the expression levels of Bax, caspase 3, and calcium\/calmodulin-dependent protein kinase II, accompanied by a down-regulated level of B-cell lymphoma-2. Exposure to this stress model reduced hippocampal glutamate ionotropic receptor N-methyl-D-aspartic acid type subunit 2A, neuronal nuclear protein, and glial fibrillary acidic protein expression levels while it raised the level of ionotropic glutamate receptor N-methyl-D-aspartic acid type subunit 2B level. It is concluded that chronic stress induces excessive glutamate release and overstimulation of N-methyl-D-aspartic acid receptors, followed by astrocytic apoptosis. Also, in depression, calcium overload in astrocytes is attributed to an underlying mechanism of astrocyte impairment.<\/jats:p>","DOI":"10.31083\/j.jin.2019.04.1164","type":"journal-article","created":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T01:19:07Z","timestamp":1578878347000},"source":"Crossref","is-referenced-by-count":19,"title":["The glutamatergic system and astrocytic impairment in rat hippocampus: a comparative study of underlying etiology and pathophysiology of depression"],"prefix":"10.31083","volume":"18","author":[{"given":"Shuo","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Acupuncture and Moxibustion, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quan-ai","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong","family":"Di","sequence":"first","affiliation":[{"name":"Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, P. R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2019,12,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Byrne, M. J., Putkey, J. A., Waxham, M. N. and Kubota, Y. (2009) Dissecting cooperative calmodulin binding to CaM kinase II: a detailed stochastic model. Journal of Computational Neuroscience 27, 621-638.","DOI":"10.1007\/s10827-009-0173-302bc3085-c485-40fd-b424-bf468d799a92http:\/\/www.springerlink.com\/content\/432r34804446175l\/"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Cotter, D., Mackay, D., Landau, S., Kerwin, R. and Everall, I. (2001) Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Archives of General Psychiatry 58, 545-553.","DOI":"10.1001\/archpsyc.58.6.54511386983https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11386983"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Deutschenbaur, L., Beck, J., Kiyhankhadiv, A., Muhlhauser, M., Borgwardt, S., Walter, M. and Lang, U. E. (2016) Role of calcium, glutamate and NMDA in major depression and therapeutic application. Progress in Neuro-psychopharmacology & Biological Psychiatry 64, 325-333.","DOI":"10.4306\/pi.2013.10.1.823482954https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23482954"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Frye, M. A., Tsai, G. E., Huggins, T., Coyle, J. T. and Post, R. M. (2007) Low cerebrospinal fluid glutamate and glycine in refractory affective disorder. Biological Psychiatry 61, 162-166.","DOI":"10.1016\/j.biopsych.2006.01.02416735030https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16735030"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Hashimoto, K., Sawa, A. and Iyo, M. (2007) Increased levels of glutamate in brains from patients with mood disorders. Biological Psychiatry 62, 1310-1316.","DOI":"10.1016\/j.biopsych.2007.03.01717574216https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17574216"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Hasler, G., van der Veen, J. W., Tumonis, T., Meyers, N., Shen, J. and Drevets, W. C. (2007) Reduced prefrontal glutamate\/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Archives of General Psychiatry 64, 193-200.","DOI":"10.1001\/archpsyc.64.2.19317283286https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17283286"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Kim, Y. K., Lee, H. P., Won, S. D., Park, E. Y., Lee, H. Y., Lee, B. H. and Choi, S. H. (2007) Low plasma BDNF is associated with suicidal behavior in major depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry 31, 78-85.","DOI":"10.4306\/pi.2013.10.1.823482954https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23482954"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Kohr, G . (2006) NMDA receptor function: subunit composition versus spatial distribution. Cell and Tissue Research 326, 439-446.","DOI":"10.1007\/s00441-006-0273-6a8893fbd-3ff6-4401-93d2-09175fe3935dhttp:\/\/www.springerlink.com\/content\/tg175445610wv196\/"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Kugaya, A. and Sanacora, G. (2005) Beyond monoamines: glutamatergic function in mood disorders. CNS Spectrums 10, 808-819.","DOI":"10.1017\/s109285290001040316400244https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16400244"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Lang, U. E. and Borgwardt, S. (2013) Molecular mechanisms of depression: perspectives on new treatment strategies. Cellular Physiology and Biochemistry 31, 761-777.","DOI":"10.1159\/0003500942845e07e-8fd5-4f27-ae44-4d5737feb71dhttp:\/\/dx.doi.org\/10.1159\/000350094"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Lebon, V., Petersen, K. F., Cline, G. W., Shen, J., Mason, G. F., Dufour, S. and Rothman, D. L. (2002) Astroglial contribution to brain energy metabolism in humans revealed by 13C nuclear magnetic resonance spectroscopy: elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. The Journal of Neuroscience 22, 1523-1531. 11880482https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11880482","DOI":"10.1523\/JNEUROSCI.22-05-01523.2002"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Li, L., Stefan, M. I. and Le Novere, N. (2012) Calcium input frequency, duration and amplitude differentially modulate the relative activation of calcineurin and CaMKII. PLoS One 7, e43810.","DOI":"10.1371\/journal.pone.004381022962589https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/22962589"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Liu, Y., Wong, T. P., Aarts, M., Rooyakkers, A., Liu, L., Lai, T. W., Wu, D. C., Lu, J., Tymianski, M., Craig, A. M. and Wang, Y. T. (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. The Journal of Neuroscience 27, 2846-2857.","DOI":"10.1523\/JNEUROSCI.0116-07.200717360906https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17360906"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Marsden, W. N. (2013) Synaptic plasticity in depression: molecular, cellular and functional correlates. Progress in Neuro-psychopharmacology & Biological Psychiatry 43, 168-184.","DOI":"10.4306\/pi.2013.10.1.823482954https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23482954"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Mauri, M. C., Ferrara, A., Boscati, L., Bravin, S., Zamberlan, F., Alecci, M. and Invernizzi, G. (1998) Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment. Neuropsychobiology 37, 124-129.","DOI":"10.1159\/0000264919597668https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/9597668"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Mitchell, N. D. and Baker, G. B. (2010) An update on the role of glutamate in the pathophysiology of depression. Acta Psychiatrica Scandinavica 122, 192-210.","DOI":"10.1111\/j.1600-0447.2009.01529.x20105149https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/20105149"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Ongur, D., Drevets, W. C. and Price, J. L. (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proceedings of the National Academy of Sciences of the United States of America 95, 13290-13295.","DOI":"10.1073\/pnas.95.22.132909789081https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/9789081"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Orrenius, S., Gogvadze, V. and Zhivotovsky, B. (2015) Calcium and mitochondria in the regulation of cell death. Biochemical and Biophysical Research Communications 460, 72-81.","DOI":"10.1016\/j.bbrc.2015.01.13725998735https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/25998735"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Orrenius, S., Zhivotovsky, B. and Nicotera, P. (2003) Regulation of cell death: the calcium apoptosis link. Nature Reviews Molecular Cell Biology 4, 552-565.","DOI":"10.1038\/nrm115012838338https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12838338"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Pavlides, C., Nivon, L. G. and McEwen, B. S. (2002) Effects of chronic stress on hippocampal long-term potentiation. Hippocampus 12, 245-257.","DOI":"10.1002\/hipo.111612000121https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12000121"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Pepke, S., Kinzer-Ursem, T., Mihalas, S. and Kennedy, M. B. (2010) A dynamic model of interactions of Ca 2+, calmodulin, and catalytic subunits of Ca 2+\/calmodulin-dependent protein kinase II . PLoS Computational Biology 6, e1000675.","DOI":"10.1371\/journal.pcbi.100067520168991https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/20168991"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Rajkowska, G., Miguel-Hidalgo, J. J., Wei, J., Dilley, G., Pittman, S. D., Meltzer, H. Y. and Stockmeier, C. A. (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biological Psychiatry 45, 1085-1098.","DOI":"10.1016\/s0006-3223(99)00041-410331101https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/10331101"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Sanacora, G., Zarate, C. A., Krystal, J. H. and Manji, H. K. (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Reviews Drug Discovery 7, 426-437.","DOI":"10.1038\/nrd246218425072https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/18425072"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S. and Hen, R. (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805-809.","DOI":"10.1126\/science.108332812907793https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12907793"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Soriano, F. X. and Hardingham, G. E. (2007) Compartmentalized NMDA receptor signalling to survival and death. The Journal of Physiology 584, 381-387.","DOI":"10.1113\/jphysiol.2007.13887517690142https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/17690142"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Yashiro, K. and Philpot, B. D. (2008) Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 55, 1081-1094.","DOI":"10.1016\/j.neuropharm.2008.07.046663525af-6107-42a9-9158-9b2010050765http:\/\/www.sciencedirect.com\/science\/article\/pii\/S0028390808003122"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Yildiz-Yesiloglu, A. and Ankerst, D. P. (2006) Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Progress in Neuro-Psychopharmacology & Biological Psychiatry 30, 969-995.","DOI":"10.4306\/pi.2013.10.1.823482954https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23482954"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Zhang, Z., Wang, C. Z., Wen, X. D., Shoyama, Y. and Yuan, C. S. (2013) Role of saffron and its constituents on cancer chemoprevention. Pharmaceutical Biology 51, 920-924.","DOI":"10.3109\/13880209.2013.77119023570520https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/23570520"}],"container-title":["Journal of Integrative Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/18\/4\/10.31083\/j.jin.2019.04.1164","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T15:08:59Z","timestamp":1732720139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/18\/4\/10.31083\/j.jin.2019.04.1164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,30]]},"references-count":28,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019]]}},"alternative-id":["1757-448X-18-4-387"],"URL":"https:\/\/doi.org\/10.31083\/j.jin.2019.04.1164","relation":{},"ISSN":["0219-6352","1757-448X"],"issn-type":[{"value":"0219-6352","type":"print"},{"value":"1757-448X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,30]]},"article-number":"387"}}