Abstract
Rationale and objective
Post-traumatic stress disorder (PTSD) is a prevalent and debilitating psychiatric disorder. However, its specific etiological mechanism remains unclear. Previous studies have shown that traumatic stress changes metabotropic glutamate receptor 5 (mGluR5) expression in the hippocampus (HIP) and prefrontal cortex (PFC). More importantly, mGluR5 expression is often accompanied by alterations in brain-derived neurotrophic factor (BDNF). Furthermore, BDNF/tropomyosin-associated kinase B (TrkB) signaling plays multiple roles, including roles in neuroplasticity and antidepressant activity, by regulating glutamate transporter-1 (GLT-1) expression. This study aims to explore the effects of inhibiting mGluR5 on PTSD-like behaviors and BDNF, TrkB, and GLT-1 expression in the HIP and PFC of inevitable foot shock (IFS)-treated rats.
Methods
Seven-day IFS was used to establish a PTSD rat model, and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (10 mg/kg, intraperitoneal injection) was used to inhibit the activity of mGluR5 during IFS in rats. After modeling, behavioral changes and mGluR5, BDNF, TrkB, and GLT-1 expression in the PFC and HIP were examined.
Results
First, the IFS procedure induced PTSD-like behavior. Second, IFS increased the expression of mGluR5 and decreased BDNF, TrkB, and GLT-1 expression in the PFC and HIP. Third, the mGluR5 antagonist blocked the above behavioral and molecular alterations.
Conclusions
mGluR5 was involved in IFS-induced PTSD-like behavior by changing BDNF, TrkB, and GLT-1 expression.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Raw data supporting the conclusions of this paper will be provided by the corresponding author upon reasonable request.
Change history
05 May 2023
A Correction to this paper has been published: https://doi.org/10.1007/s00213-023-06368-w
Abbreviations
- MPEP:
-
2-Methyl-6-(phenylethynyl)-pyridine
- BDNF:
-
Brain-derived neurotrophic factor
- GLT-1:
-
Glutamate transporter-1
- HIP:
-
Hippocampus
- IFS:
-
Inevitable foot shock
- LTP:
-
Long-term potentiation
- mPFC:
-
Medial prefrontal cortex
- mGluR:
-
Metabotropic glutamate receptor
- PCR:
-
Polymerase chain reaction
- PTSD:
-
Post-traumatic stress disorder
- PFC:
-
Prefrontal cortex
- TrkB:
-
Tropomyosin-associated kinase B
References
Andero R, Choi DC, Ressler KJ (2014) BDNF-TrkB receptor regulation of distributed adult neural plasticity, memory formation, and psychiatric disorders. Prog Mol Biol Transl Sci 122:169–192. https://doi.org/10.1016/B978-0-12-420170-5.00006-4
Asim M, Wang B, Hao B, Wang X (2021) Ketamine for post-traumatic stress disorders and it’s possible therapeutic mechanism. Neurochem Int 146:105044. https://doi.org/10.1016/j.neuint.2021.105044
Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64:238–258. https://doi.org/10.1124/pr.111.005108
Bali A, Jaggi AS (2015) Electric foot shock stress: a useful tool in neuropsychiatric studies. Rev Neurosci 26:655–677. https://doi.org/10.1515/revneuro-2015-0015
Borghans B, Homberg JR (2015) Animal models for posttraumatic stress disorder: an overview of what is used in research. World J Psychiatr 5:387–396. https://doi.org/10.5498/wjp.v5.i4.387
Chang S-H, Yu YH, He A et al (2021) BDNF protein and BDNF mRNA expression of the medial prefrontal cortex, amygdala, and hippocampus during situational reminder in the PTSD animal model. Behav Neurol 2021:6657716. https://doi.org/10.1155/2021/6657716
Colucci-D’Amato L, Speranza L, Volpicelli F (2020) Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int J Mol Sci 21:7777. https://doi.org/10.3390/ijms21207777
DomitrovicSpudic S, NikolacPerkovic M, Uzun S et al (2022) Reduced plasma BDNF concentration and cognitive decline in veterans with PTSD. Psychiatr Res 316:114772. https://doi.org/10.1016/j.psychres.2022.114772
Esterlis I, DellaGioia N, Pietrzak RH et al (2018) Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression. Mol Psychiatr 23:824–832. https://doi.org/10.1038/mp.2017.58
Feng D, Guo B, Liu G et al (2015) FGF2 alleviates PTSD symptoms in rats by restoring GLAST function in astrocytes via the JAK/STAT pathway. Eur Neuropsychopharmacol 25:1287–1299. https://doi.org/10.1016/j.euroneuro.2015.04.020
Fenster RJ, Lebois LAM, Ressler KJ, Suh J (2018) Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man. Nat Rev Neurosci 19:535–551. https://doi.org/10.1038/s41583-018-0039-7
Fraga DB, Costa AP, Olescowicz G et al (2020) Ascorbic acid presents rapid behavioral and hippocampal synaptic plasticity effects. Progress Neuro-Psychopharmacol Biol Psychiatr 96:109757. https://doi.org/10.1016/j.pnpbp.2019.109757
Garcia-Keller C, Carter JS, Kruyer A et al (2021) Behavioral and accumbens synaptic plasticity induced by cues associated with restraint stress. Neuropsychopharmacology 46:1848–1856. https://doi.org/10.1038/s41386-021-01074-7
Holmes SE, Girgenti MJ, Davis MT et al (2017) Altered metabotropic glutamate receptor 5 markers in PTSD: in vivo and postmortem evidence. Proc Natl Acad Sci U S A 114:8390–8395. https://doi.org/10.1073/pnas.1701749114
Homiack D, O’Cinneide E, Hajmurad S et al (2018) Effect of acute alarm odor exposure and biological sex on generalized avoidance and glutamatergic signaling in the hippocampus of Wistar rats. Stress 21:292–303. https://doi.org/10.1080/10253890.2018.1484099
Iijima M, Fukumoto K, Chaki S (2012) Acute and sustained effects of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test. Behav Brain Res 235:287–292. https://doi.org/10.1016/j.bbr.2012.08.016
Ismayilova N, Verkhratsky A, Dascombe MJ (2006) Changes in mGlu5 receptor expression in the basal ganglia of reserpinised rats. Eur J Pharmacol 545:134–141. https://doi.org/10.1016/j.ejphar.2006.06.076
Ji Y-F, Zhou L, Xie Y-J et al (2013) Upregulation of glutamate transporter GLT-1 by mTOR-Akt-NF-кB cascade in astrocytic oxygen-glucose deprivation: enhanced GLT-1 by mTOR-Akt-NF-кB Cascade. Glia 61:1959–1975. https://doi.org/10.1002/glia.22566
Jia N, Li Q, Sun H et al (2015) Alterations of group I mGluRs and BDNF associated with behavioral abnormity in prenatally stressed offspring rats. Neurochem Res 40:1074–1082. https://doi.org/10.1007/s11064-015-1565-6
Jiang X, Lin W, Cheng Y, Wang D (2020) mGluR5 facilitates long-term synaptic depression in a stress-induced depressive mouse model. Can J Psychiatr 65:347–355. https://doi.org/10.1177/0706743719874162
Koenen KC, Ratanatharathorn A, Ng L et al (2017) Posttraumatic stress disorder in the World Mental Health Surveys. Psychol Med 47:2260–2274. https://doi.org/10.1017/S0033291717000708
Kraeuter AK, Guest PC, Sarnyai Z (2019) The Y-Maze for assessment of spatial working and reference memory in mice. Methods Mol Biol 1916:105–111. https://doi.org/10.1007/978-1-4939-8994-2_10
Legutko B, Szewczyk B, Pomierny-Chamio L, Nowak G, Pilc A (2006) Effect of MPEP treatment on brain-derived neurotrophic factor gene expression. Pharmacol Rep 58(3):427–430
Li Y-K, Wang F, Wang W et al (2012) Aquaporin-4 deficiency impairs synaptic plasticity and associative fear memory in the lateral amygdala: involvement of downregulation of glutamate transporter-1 expression. Neuropsychopharmacology 37:1867–1878. https://doi.org/10.1038/npp.2012.34
Li M-X, Li Q, Sun X-J et al (2019) Increased Homer1-mGluR5 mediates chronic stress-induced depressive-like behaviors and glutamatergic dysregulation via activation of PERK-eIF2α. Progress Neuro-Psychopharmacol Biol Psychiatr 95:109682. https://doi.org/10.1016/j.pnpbp.2019.109682
Li M, Xie Y, Niu K, Li K (2020) Electroacupuncture ameliorates post-traumatic stress disorder in rats via a mechanism involving the BDNF-TrkB signaling pathway. Cell Mol Biol (Noisy-le-grand) 66:165–170
Liu CY, Jiang XX, Zhu YH, Wei DN (2012) Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine produces antidepressant effects in rats: role of brain-derived neurotrophic factor. Neuroscience 223:219–224. https://doi.org/10.1016/j.neuroscience.2012.08.010
Liu W-X, Wang J, Xie Z-M et al (2016) Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression. Psychopharmacology 233:405–415. https://doi.org/10.1007/s00213-015-4128-2
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Mahan AL, Ressler KJ (2012) Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35:24–35. https://doi.org/10.1016/j.tins.2011.06.007
Mao L-M, Wang JQ (2018) Alterations in mGlu5 receptor expression and function in the striatum in a rat depression model. J Neurochem 145:287–298. https://doi.org/10.1111/jnc.14307
McNair LF, Andersen JV, Aldana BI et al (2019) Deletion of neuronal GLT-1 in mice reveals its role in synaptic glutamate homeostasis and mitochondrial function. J Neurosci 39:4847–4863. https://doi.org/10.1523/JNEUROSCI.0894-18.2019
Miller MW, Sadeh N (2014) Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis. Mol Psychiatry 19:1156–1162. https://doi.org/10.1038/mp.2014.111
Miranda M, Morici JF, Zanoni MB, Bekinschtein P (2019) Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci 13:363. https://doi.org/10.3389/fncel.2019.00363
Myers KM, Carlezon WA, Davis M (2011) Glutamate receptors in extinction and extinction-based therapies for psychiatric illness. Neuropsychopharmacology 36:274–293. https://doi.org/10.1038/npp.2010.88
Notaras M, van den Buuse M (2020) Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders. Mol Psychiatr 25:2251–2274. https://doi.org/10.1038/s41380-019-0639-2
Pajarillo E, Rizor A, Lee J et al (2019) The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: potential targets for neurotherapeutics. Neuropharmacology 161:107559. https://doi.org/10.1016/j.neuropharm.2019.03.002
Pignatelli M, Vollmayr B, Richter SH et al (2013) Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats. Neuropharmacology 66:339–347. https://doi.org/10.1016/j.neuropharm.2012.05.046
Pilc A, Kłodzińska A, Brański P et al (2002) Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats. Neuropharmacology 43:181–187. https://doi.org/10.1016/S0028-3908(02)00082-5
Pokusa M, Prokopova B, Hlavacova N et al (2014) Effect of blockade of mGluR5 on stress hormone release and its gene expression in the adrenal gland. Can J Physiol Pharmacol 92:686–692. https://doi.org/10.1139/cjpp-2014-0030
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33. https://doi.org/10.1016/S0014-2999(03)01272-X
Ren L, Tao W, Zhang H et al (2016) Two standardized fractions of Gardenia jasminoides Ellis with rapid antidepressant effects are differentially associated with BDNF up-regulation in the hippocampus. J Ethnopharmacol 187:66–73. https://doi.org/10.1016/j.jep.2016.04.023
Richter-Levin G, Stork O, Schmidt MV (2019) Animal models of PTSD: a challenge to be met. Mol Psychiatr 24:1135–1156. https://doi.org/10.1038/s41380-018-0272-5
Rimmele TS, Li S, Andersen JV et al (2021) Neuronal loss of the glutamate transporter GLT-1 promotes excitotoxic injury in the hippocampus. Front Cell Neurosci 15:788262. https://doi.org/10.3389/fncel.2021.788262
Robinson S, Mogul AS, Taylor-Yeremeeva EM et al (2021) Stress diminishes BDNF-stimulated TrkB signaling, TrkB-NMDA receptor linkage and neuronal activity in the rat brain. Neuroscience 473:142–158. https://doi.org/10.1016/j.neuroscience.2021.07.011
Schulz B, Fendt M, Gasparini F et al (2001) The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats. Neuropharmacology 41:1–7. https://doi.org/10.1016/S0028-3908(01)00036-3
Sethna F, Wang H (2016) Acute inhibition of mGluR5 disrupts behavioral flexibility. Neurobiol Learn Mem 130:1–6. https://doi.org/10.1016/j.nlm.2016.01.004
Shafia S, Vafaei AA, Samaei SA et al (2017) Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis – related proteins in a rat model of post-traumatic stress disorder. Neurobiol Learn Mem 139:165–178. https://doi.org/10.1016/j.nlm.2017.01.009
Sun H, Su R, Zhang X et al (2017) Hippocampal GR- and CB1-mediated mGluR5 differentially produces susceptibility and resilience to acute and chronic mild stress in rats. Neuroscience 357:295–302. https://doi.org/10.1016/j.neuroscience.2017.06.017
Tatarczyńska E, Kłodzińska A, Chojnacka-Wójcik E et al (2001) Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 132:1423–1430. https://doi.org/10.1038/sj.bjp.0703923
Tong L, Li M-D, Nie P-Y et al (2021) miR-132 downregulation alleviates behavioral impairment of rats exposed to single prolonged stress, reduces the level of apoptosis in PFC, and upregulates the expression of MeCP2 and BDNF. Neurobiol Stress 14:. https://doi.org/10.1016/j.ynstr.2021.100311
Verbitsky A, Dopfel D, Zhang N (2020) Rodent models of post-traumatic stress disorder: behavioral assessment. Transl Psychiatr 10:1–28. https://doi.org/10.1038/s41398-020-0806-x
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2:322. https://doi.org/10.1038/nprot.2007.44
Wang Y, He W, Zhang H et al (2020) mGluR5 mediates ketamine antidepressant response in susceptible rats exposed to prenatal stress. J Affect Disord 272:398–408. https://doi.org/10.1016/j.jad.2020.03.104
Wang W, Wang R, Jiang Z et al (2021) Inhibiting Brd4 alleviated PTSD-like behaviors and fear memory through regulating immediate early genes expression and neuroinflammation in rats. J Neurochem 158:912–927. https://doi.org/10.1111/jnc.15439
Yang F, Wang H, Chen H et al (2020) RAGE Signaling pathway in hippocampus dentate gyrus involved in GLT-1 decrease induced by chronic unpredictable stress in rats. Brain Res Bull 163:49–56. https://doi.org/10.1016/j.brainresbull.2020.06.020
Yap JJ, Covington HE, Gale MC et al (2005) Behavioral sensitization due to social defeat stress in mice: antagonism at mGluR5 and NMDA receptors. Psychopharmacology 179:230–239. https://doi.org/10.1007/s00213-004-2023-3
Zhang X, Zhao Y, Du Y et al (2021) Effect of ketamine on mood dysfunction and spatial cognition deficits in PTSD mouse models via HCN1–BDNF signaling. J Affect Disord 286:248–258. https://doi.org/10.1016/j.jad.2021.02.058
Zhang X-Y, Wei W, Zhang Y-Z, et al (2018) The 18 kDa translocator protein (TSPO) overexpression in hippocampal dentate gyrus elicits anxiolytic-like effects in a mouse model of post-traumatic stress disorder. Frontiers in Pharmacology 9:
Zhao M, Zhu Z, Li H et al (2022) Effects of traumatic stress in adolescence on PTSD-like behaviors, dendrite development, and H3K9me2/BDNF expression in the amygdala of male rats. J Affect Disord 296:388–399. https://doi.org/10.1016/j.jad.2021.09.101
Funding
This work was supported by the National Natural Science Foundation of China (no. 31771220).
Author information
Authors and Affiliations
Contributions
S.C. and J.X. performed the major experiments, data analysis, and wrote the manuscripts; R.W., W.W., H.L., and Z.J. established the biophysical model, S.C., J.X., and F.P. designed this study; D.L. and F.P. revised the paper.
Corresponding author
Ethics declarations
Ethical approval
The animal study was reviewed and approved by the Animal Ethics Committee of Shandong University.
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Shuyue Cheng and Jingjing Xu have contributed equally to this work and share the first authorship.
The original version of this article was revised: This article was originally published with the Figure 6E, image of the prefrontal cortex in the PTSD+M group being misused.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Cheng, S., Xu, J., Wang, W. et al. Inhibition of mGluR5 alters BDNF/TrkB and GLT-1 expression in the prefrontal cortex and hippocampus and ameliorates PTSD-like behavior in rats. Psychopharmacology 240, 837–851 (2023). https://doi.org/10.1007/s00213-023-06325-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-023-06325-7