Skip to main content

Advertisement

SpringerLink
Log in

Matrix Metalloproteinase-9 Overexpression Regulates Hippocampal Synaptic Plasticity and Decreases Alcohol Consumption and Preference in Mice

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Brain matrix metalloproteinases (MMPs) have been recently implicated in alcohol addiction; however, the molecular mechanisms remain poorly understood. Matrix metalloproteinase-9 (MMP-9), an extrasynaptic protease, is the best described MMP that is thought to regulate addictive behavior. In the present study, the effect of MMP-9 overexpression on hippocampal neuron plasticity and alcoholic behavior was assessed in spontaneous alcohol drinking mice. Two-bottle choice model showed that the overexpression of MMP-9 in the hippocampus developed by adeno-associated virus (AAV) could decrease alcohol consumption and preference, but did not affect taste preference, which was tested using saccharin or quinine solutions. Dendritic spines number of hippocampal neurons was observed by Golgi staining. Compared with the alcohol treatment group, the density of dendritic spines in the hippocampus of alcohol drinking mice was decreased in alcohol + MMP-9 group. Western blot analysis indicated that GluN1 expression in the hippocampus of alcohol drinking group was lower than that in the control group, while the expression of GluN1 was increased in MMP-9 overexpressing mice. MMP-9 also regulated the depolymerization of actin filaments, which induced behavioral changes in mice. Taken together, overexpression of MMP-9 in the hippocampal neurons of mice resulted in decreased dendritic spine density and F-actin/G-actin ratio, which might be the crucial reason for the significant decrease in alcohol consumption in alcohol drinking mice. MMP-9 might be considered as a novel target studying the molecular mechanism of alcohol drinking.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3(8):760–773

    PubMed  PubMed Central  Google Scholar 

  2. Ponomarev I, Wang S, Zhang L, Harris RA, Mayfield RD (2012) Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J Neurosci 32(5):1884–1897

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Cozzoli DK, Courson J, Wroten MG, Greentree DI, Lum EN, Campbell RR, Thompson AB, Maliniak D, Worley PF, Jonquieres G, Klugmann M, Finn DA, Szumlinski KK (2014) Binge alcohol drinking by mice requires intact group 1 metabotropic glutamate receptor signaling within the central nucleus of the amygdala. Neuropsychopharmacology 39(2):435–444

    CAS  PubMed  Google Scholar 

  4. Labots M, Cousijn J, Jolink LA, Kenemans JL, Vanderschuren LJMJ, Lesscher HMB (2018) Age-related differences in alcohol intake and control over alcohol seeking in rats. Front Psychiatry 9:419

    PubMed  PubMed Central  Google Scholar 

  5. Farris SP, Harris RA, Ponomarev I (2015) Epigenetic modulation of brain gene networks for cocaine and alcohol abuse. Front Neurosci 9:176

    PubMed  PubMed Central  Google Scholar 

  6. Ben Hamida S, Mendonca-Netto S, Arefin TM, Nasseef MT, Boulos LJ, McNicholas M, Ehrlich AT, Clarke E, Moquin L, Gratton A, Darcq E, Harsan LA, Maldonado R, Kieffer BL (2018) Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks. Biol Psychiatry 84(3):202–212

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Stawarski M, Stefaniuk M, Wlodarczyk J (2014) Matrix metalloproteinase-9 involvement in the structural plasticity of dendritic spines. Front Neuroanat 8:68

    PubMed  PubMed Central  Google Scholar 

  8. Beckley JT, Laguesse S, Phamluong K, Morisot N, Wegner SA, Ron D (2016) The first alcohol drink triggers mTORC1-dependent synaptic plasticity in nucleus accumbens dopamine D1 receptor neurons. J Neurosci 36(3):701–713

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nestler EJ (2002) Common molecular and cellular substrates of addiction and memory. Neurobiol Learn Mem 78(3):637–647

    CAS  PubMed  Google Scholar 

  10. Wright VL, Georgiou P, Bailey A, Heal DJ, Bailey CP, Wonnacott S (2019) Inhibition of alpha7 nicotinic receptors in the ventral hippocampus selectively attenuates reinstatement of morphine-conditioned place preference and associated changes in AMPA receptor binding. Addict Biol 24(4):590–603

    CAS  PubMed  Google Scholar 

  11. Lovinger DM, Abrahao KP (2018) Synaptic plasticity mechanisms common to learning and alcohol use disorder. Learn Mem 25(9):425–434

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang W, Zhu PJ, Zhang S, Zhou H, Stoica L, Galiano M, Krnjevic K, Roman G, Costa-Mattioli M (2013) mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci 16(4):441–448

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Li D, Jing D, Liu Z, Chen Y, Huang F, Behnisch T (2019) Enhanced expression of secreted alpha-klotho in the hippocampus alters nesting behavior and memory formation in mice. Front Cell Neurosci 13:133

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Dziembowska M, Wlodarczyk J (2012) MMP9: a novel function in synaptic plasticity. Int J Biochem Cell Biol 44(5):709–713

    CAS  PubMed  Google Scholar 

  15. Vafadari B, Salamian A, Kaczmarek L (2016) MMP-9 in translation: from molecule to brain physiology, pathology, and therapy. J Neurochem 139:91–114

    CAS  PubMed  Google Scholar 

  16. Murase S, Lantz CL, Kim E, Gupta N, Higgins R, Stopfer M, Hoffman DA, Quinlan EM (2016) Matrix metalloproteinase-9 regulates neuronal circuit development and excitability. Mol Neurobiol 53(5):3477–3493

    CAS  PubMed  Google Scholar 

  17. Jasińska M, Miłek J, Cymerman IA, Łęski S, Kaczmarek L, Dziembowska M (2015) miR-132 regulates dendritic spine structure by direct targeting of matrix metalloproteinase 9 mRNA. Mol Neurobiol 53(7):4701–4712

    PubMed  PubMed Central  Google Scholar 

  18. Beroun A, Mitra S, Michaluk P, Pijet B, Stefaniuk M, Kaczmarek L (2019) MMPs in learning and memory and neuropsychiatric disorders. Cell Mol Life Sci 76(16):3207–3228

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Stefaniuk M, Beroun A, Lebitko T, Markina O, Leski S, Meyza K, Grzywacz A, Samochowiec J, Samochowiec A, Radwanska K, Kaczmarek L (2017) Matrix metalloproteinase-9 and synaptic plasticity in the central amygdala in control of alcohol-seeking behavior. Biol Psychiatry 81(11):907–917

    CAS  PubMed  Google Scholar 

  20. Samochowiec A, Grzywacz A, Kaczmarek L, Bienkowski P, Samochowiec J, Mierzejewski P, Preuss UW, Grochans E, Ciechanowicz A (2010) Functional polymorphism of matrix metalloproteinase-9 (MMP-9) gene in alcohol dependence: family and case control study. Brain Res 1327:103–106

    CAS  PubMed  Google Scholar 

  21. Bahi A, Dreyer JL (2013) Striatal modulation of BDNF expression using microRNA124a-expressing lentiviral vectors impairs ethanol-induced conditioned-place preference and voluntary alcohol consumption. Eur J Neurosci 38(2):2328–2337

    PubMed  Google Scholar 

  22. Al Mansouri S, Ojha S, Al Maamari E, Al Ameri M, Nurulain SM, Bahi A (2014) The cannabinoid receptor 2 agonist, beta-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice. Pharmacol Biochem Behav 124:260–268

    CAS  PubMed  Google Scholar 

  23. Korobova F, Svitkina T (2010) Molecular architecture of synaptic actin cytoskeleton in hippocampal neurons reveals a mechanism of dendritic spine morphogenesis. Mol Biol Cell 21(1):165–176

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35(1):217–238

    PubMed  Google Scholar 

  25. Mews P, Egervari G, Nativio R, Sidoli S, Donahue G, Lombroso SI, Alexander DC, Riesche SL, Heller EA, Nestler EJ, Garcia BA, Berger SL (2019) Alcohol metabolism contributes to brain histone acetylation. Nature 574(7780):717–721

    CAS  PubMed  PubMed Central  Google Scholar 

  26. D'Souza MS (2015) Glutamatergic transmission in drug reward: implications for drug addiction. Front Neurosci 9:404

    PubMed  PubMed Central  Google Scholar 

  27. Morisot N, Berger AL, Phamluong K, Cross A, Ron D (2018) The Fyn kinase inhibitor, AZD0530, suppresses mouse alcohol self-administration and seeking. Addict Biol 24(6):1227–1234

    PubMed  Google Scholar 

  28. Mielenz D, Reichel M, Jia T, Quinlan EB, Stockl T, Mettang M, Zilske D, Kirmizi-Alsan E, Schonberger P, Praetner M, Huber SE, Amato D, Schwarz M, Purohit P, Brachs S, Spranger J, Hess A, Buttner C, Ekici AB, Perez-Branguli F, Winner B, Rauschenberger V, Banaschewski T, Bokde ALW, Buchel C, Conrod PJ, Desrivieres S, Flor H, Frouin V, Gallinat J, Garavan H, Gowland P, Heinz A, Martinot JL, Lemaitre H, Nees F, Paus T, Smolka MN, Consortium I, Schambony A, Bauerle T, Eulenburg V, Alzheimer C, Lourdusamy A, Schumann G, Muller CP. 2018. EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction. Mol Psychiatry, 23(5): 1303-1319.

  29. Smith ACW, Scofield MD, Kalivas PW (2015) The tetrapartite synapse: extracellular matrix remodeling contributes to corticoaccumbens plasticity underlying drug addiction. Brain Res 1628:29–39

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Garcia-Keller C, Neuhofer D, Bobadilla AC, Spencer S, Chioma VC, Monforton C, Kalivas PW (2019) Extracellular matrix signaling through beta3 integrin mediates cocaine cue-induced transient synaptic plasticity and relapse. Biol Psychiatry 86(5):377–387

    CAS  PubMed  Google Scholar 

  31. Yin L, Li F, Li J, Yang X, Xie X, Xue L, Li Y, Zhang C (2019) Chronic intermittent ethanol exposure induces upregulation of matrix metalloproteinase-9 in the rat medial prefrontal cortex and hippocampus. Neurochem Res 44(7):1593–1601

    CAS  PubMed  Google Scholar 

  32. Smith AW, Nealey KA, Wright JW, Walker BM (2011) Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems. Neurobiol Learn Mem 96(2):199–206

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Smith ACW (2017) A Glitch in the matrix: aberrant extracellular matrix proteolysis contributes to alcohol seeking. Biol Psychiatry 81(11):900–902

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Britt JP, Benaliouad F, McDevitt RA, Stuber GD, Wise RA, Bonci A (2012) Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron 76(4):790–803

    CAS  PubMed  PubMed Central  Google Scholar 

  35. O'Donnell P, Grace AA (1995) Synaptic interactions among excitatory afferents to nucleus accumbens neurons: hippocampal gating of prefrontal cortical input. J Neurosci 15(5 Pt 1):3622–3639

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Loureiro M, Kramar C, Renard J, Rosen LG, Laviolette SR (2016) Cannabinoid transmission in the hippocampus activates nucleus accumbens neurons and modulates reward and aversion-related emotional salience. Biol Psychiatry 80(3):216–225

    CAS  PubMed  Google Scholar 

  37. Kondratiuk I, Leski S, Urbanska M, Biecek P, Devijver H, Lechat B, Van Leuven F, Kaczmarek L, Jaworski T (2017) GSK-3beta and MMP-9 cooperate in the control of dendritic spine morphology. Mol Neurobiol 54(1):200–211

    CAS  PubMed  Google Scholar 

  38. Penalver A, Campos-Sandoval JA, Blanco E, Cardona C, Castilla L, Martin-Rufian M, Estivill-Torrus G, Sanchez-Varo R, Alonso FJ, Perez-Hernandez M, Colado MI, Gutierrez A, de Fonseca FR, Marquez J (2017) Glutaminase and MMP-9 downregulation in cortex and hippocampus of LPA1 receptor null mice correlate with altered dendritic spine plasticity. Front Mol Neurosci 10:278

    PubMed  PubMed Central  Google Scholar 

  39. Michaluk P, Wawrzyniak M, Alot P, Szczot M, Wyrembek P, Mercik K, Medvedev N, Wilczek E, De Roo M, Zuschratter W, Muller D, Wilczynski GM, Mozrzymas JW, Stewart MG, Kaczmarek L, Wlodarczyk J (2011) Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology. J Cell Sci 124(Pt 19):3369–3380

    CAS  PubMed  Google Scholar 

  40. Carpenter-Hyland EP, Chandler LJ (2007) Adaptive plasticity of NMDA receptors and dendritic spines: implications for enhanced vulnerability of the adolescent brain to alcohol addiction. Pharmacol Biochem Behav 86(2):200–208

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Miguens M, Kastanauskaite A, Coria SM, Selvas A, Ballesteros-Yanez I, DeFelipe J, Ambrosio E (2015) The effects of cocaine self-administration on dendritic spine density in the rat hippocampus are dependent on genetic background. Cereb Cortex 25(1):56–65

    PubMed  Google Scholar 

  42. Jin Z, Bhandage AK, Bazov I, Kononenko O, Bakalkin G, Korpi ER, Birnir B (2014) Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics. Front Cell Neurosci 8:11

    PubMed  PubMed Central  Google Scholar 

  43. Michaluk P, Mikasova L, Groc L, Frischknecht R, Choquet D, Kaczmarek L (2009) Matrix metalloproteinase-9 controls NMDA receptor surface diffusion through integrin beta 1 signaling. J Neurosci 29(18):6007–6012

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hotulainen P, Hoogenraad CC (2010) Actin in dendritic spines: connecting dynamics to function. J Cell Biol 189(4):619–629

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Martin JA, Werner CT, Mitra S, Zhong P, Wang ZJ, Gobira PH, Stewart AF, Zhang J, Erias K, Siemian JN, Hagarty D, Mueller LE, Neve RL, Li JX, Chandra R, Dietz KC, Lobo MK, Gancarz AM, Yan Z, Dietz DM (2019) A novel role for the actin-binding protein drebrin in regulating opiate addiction. Nat Commun 10(1):4140

    PubMed  PubMed Central  Google Scholar 

  46. Han Y, Wang X, Chen J, Sha SH (2015) Noise-induced cochlear F-actin depolymerization is mediated via ROCK2/p-ERM signaling. J Neurochem 133(5):617–628

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Oleinik NV, Krupenko NI, Krupenko SA (2010) ALDH1L1 inhibits cell motility via dephosphorylation of cofilin by PP1 and PP2A. Oncogene 29(47):6233–6244

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Caroni P, Donato F, Muller D (2012) Structural plasticity upon learning: regulation and functions. Nat Rev Neurosci 13(7):478–490

    CAS  PubMed  Google Scholar 

  49. Tian L, Stefanidakis M, Ning L, Van Lint P, Nyman-Huttunen H, Libert C, Itohara S, Mishina M, Rauvala H, Gahmberg CG (2007) Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage. J Cell Biol 178(4):687–700

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Yuanyuan J, Junyan Z, Cuola D, Jingjing C, Yuhui S, Dan X, Wei D, Yongsheng Z (2018) Memantine attenuated alcohol withdrawal-induced anxiety-like behaviors through down-regulating NR1-CaMKII-ERK signaling pathway. Neurosci Lett 686:133–139

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81601167), the Postgraduate Innovation Foundation of Shanxi Province, China (No. 2019SY237), the Natural Science Foundation of Shanxi Province, China (No. 2013021022–1 and No. 201801D121316), and the Fund for Shanxi “1331 Project” Key Subjects Construction, China (1331KSC, No. XK201708).

Author information

Authors and Affiliations

  1. Key Laboratory for Cellular Physiology, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, 030001, Shanxi, China

    Li- Tian Yin, Xiao-Yan Xie, Lin-Yuan Xue, Xiao- Rong Yang, Yu Zhang & Ce Zhang

  2. School of Forensic Medicine, Shanxi Medical University, Taiyuan, 030001, Shanxi, China

    Juan Jia

Authors
  1. Li- Tian Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Yan Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin-Yuan Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao- Rong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ce Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LTY and XYX have contributed equally to this work.

Corresponding authors

Correspondence to Li- Tian Yin or Ce Zhang.

Ethics declarations

Conflict of interest

All authors declare that there are no conflicts of interest.

Statement Involving Animal Rights

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, L.T., Xie, XY., Xue, LY. et al. Matrix Metalloproteinase-9 Overexpression Regulates Hippocampal Synaptic Plasticity and Decreases Alcohol Consumption and Preference in Mice. Neurochem Res 45, 1902–1912 (2020). https://doi.org/10.1007/s11064-020-03053-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-020-03053-8

Keywords

Search

Navigation