Skip to main content
SpringerLink
Log in

Overstimulation of Glutamate Signals Leads to Hippocampal Transcriptional Plasticity in Hamsters

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

It’s known that neurons in mammalian hibernators are more tolerant to hypoxia than those in non-hibernating species and as a consequence animals are capable of awakening from the arousal state without exhibiting cerebral damages. In addition, evidences have suggested that euthermic hamster neurons display protective adaptations against hypoxia, while those of rats are not capable, even though molecular mechanisms involved in similar neuroprotective strategies have not been yet fully studied. In the present work, overstimulation of glutamatergic receptors NMDA recognized as one of the major death-promoting element in hypoxia, accounted for altered network complexity consistent with a moderate reduction of hippocampal neuronal survival (p < 0.05) in hamsters. These alterations appeared to be featured concomitantly with altered glutamatergic signaling as indicated by significant down-regulation (p < 0.01) of NMDAergic (NR2A) and AMPAergic (GluR1, R2) receptor subtypes together with the metabotropic mGluR5 subtype. Diminished mRNA levels were also reported for NMDA receptor binding factors and namely PSD95 plus DREAM, which exert positive and negative regulatory properties, respectively, on receptor trafficking events. Conversely, involvement of glutamatergic signaling systems on neuronal excitotoxicity was strengthened by the co-activation of GABAAR-mediated effects as indicated by toxic morphological effects being notably reduced along with up-regulated GluR1, GluR2, mGluR5, DREAM, and Homer1c scaffold proteins when muscimol was added. Overall, these results point to a neuroprotective role of the GABAergic system against excitotoxicity episodes via DREAM-dependent inhibition of NMDA receptor and activation of AMPA receptor plus mGluR5, respectively, thus proposing them as novel therapeutic targets against cerebral ischemic damages in humans.

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

Similar content being viewed by others

Abbreviations

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid

AMPAR:

Alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid receptor

DIV:

Day in vitro

DREAM:

Downstream regulatory element antagonist modulators

GABA:

γ-aminobutyric acid type

GABAAR:

γ-aminobutyric acid type A receptor

Glu:

Glutamate

GluR:

Glutamate receptor

mGluR5:

Metabotropic glutamate receptor 5

MUS:

Muscimol

NMDA:

N-methyl-D-aspartate

NMDAR:

N-methyl-D-aspartate receptor

PSD95:

Post-synaptic density 95

SEM:

Scanning electron microscopy

References

  • Al-Hallaq RA, Conrads TP, Veenstra TD, Wenthold RJ (2007) NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus. J Neurosci 27(31):8334–8343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Besancon E, Guo S, Lok J, Tymianski M, Lo EH (2008) Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci 29(5):268–275

    Article  CAS  PubMed  Google Scholar 

  • Bickler PE, Donohoe PH, Buck LT (2000) Hypoxia-induced silencing of NMDA receptors in turtle neurons. J Neurosci 20(10):3522–3528

    CAS  PubMed  Google Scholar 

  • Brewer LD, Thibault O, Staton J, Thibault V, Rogers JT, Garcia-Ramos G, Kraner S, Landfield PW, Porter NM (2007) Increased vulnerability of hippocampal neurons with age in culture: temporal association with increases in NMDA receptor current, NR2A subunit expression and recruitment of L-type calcium channels. Brain Res 1151:20–31

    Article  CAS  PubMed  Google Scholar 

  • Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40(5):e331–e339

    Article  PubMed  Google Scholar 

  • Calabresi P, Cupini LM, Centonze D, Pisani F, Bernardi G (2003) Antiepileptic drugs as a possible neuroprotective strategy in brain ischemia. Ann Neurol 53:693–702

    Article  CAS  PubMed  Google Scholar 

  • Chen WF, Chang H, Huang LT, Lai MC, Yang CH, Wan TH, Yang SN (2006) Alterations in long-term seizure susceptibility and the complex of PSD95 with NMDA receptor from animals previously exposed to perinatal hypoxia. Epilepsia 47(2):288–296

    Article  PubMed  Google Scholar 

  • Dave KR, Christian SL, Perez-Pinzon MA, Drew KL (2012) Neuroprotection: lessons from hibernators. Comp Biochem Physiol B Biochem Mol Biol 162(1–3):1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Vito A, Giusi G, Alò R, Piscioneri A, Morelli S, De Bartolo L, Canonaco M (2011) Distinct α GABA(A)R subunits influence structural and transcriptional properties of CA1 hippocampal neurons. Neurosci Lett 496(2):106–110

    Article  PubMed  Google Scholar 

  • Duric V, Banasr M, Stockmeier CA, Simen AA, Newton SS, Overholser JC, Jurjus GJ, Dieter L, Duman RS (2013) Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 16(1):69–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edling Y, Ingelman-Sundberg M, Simi A (2007) Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM. Glia 55(3):328–340

    Article  PubMed  Google Scholar 

  • Engin E, Liu J, Rudolph U (2012) α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders. Pharmacol Ther 136(2):142–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan J, Vasuta OC, Zhang LY, Wang L, George A, Raymond LA (2010) N-methyl-D-aspartate receptor subunit- and neuronal-type dependence of excitotoxic signaling through post-synaptic density 95. Neurochem 115(4):1045–1056

    Article  CAS  Google Scholar 

  • Giusi G, Facciolo RM, Rende M, Alo R, Di Vito A, Salerno S, Morelli S, De Bartolo L, Drioli E, Canonaco M (2009) Distinct alpha subunits of the GABA(A) receptor are responsible for early hippocampal silent neuron-related activities. Hippocampus 19:1103–1114

    Article  CAS  PubMed  Google Scholar 

  • Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682–696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jara JH, Singh BB, Floden AM, Combs CK (2007) Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death. J Neurochem 100(5):1407–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang X, Mu D, Biran V, Faustino J, Chang S, Rincón CM, Sheldon RA, Ferriero DM (2008) Activated Src kinases interact with the N-methyl-D-aspartate receptor after neonatal brain ischemia. Ann Neurol 63(5):632–641

    Article  CAS  PubMed  Google Scholar 

  • Johnston MV (2005) Excitotoxicity in perinatal brain injury. Brain Pathol 15(3):234–240

    Article  CAS  PubMed  Google Scholar 

  • Kwak S, Weiss JH (2006) Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr Opin Neurobiol 16(3):281–287

    Article  CAS  PubMed  Google Scholar 

  • Lacey CJ, Bryant A, Brill J, Huguenard JR (2012) Enhanced NMDA receptor-dependent thalamic excitation and network oscillations in stargazer mice. J Neurosci 32(32):11067–11081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu SJ, Zukin RS (2007) Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci 30(3):126–134

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Zhao W, Xu T, Pei D, Peng Y (2010) Alterations of NMDA receptor subunits NR1, NR2A and NR2B mRNA expression and their relationship to apoptosis following transient forebrain ischemia. Brain Res 1361:133–139

    Article  CAS  PubMed  Google Scholar 

  • Lu W, Shi Y, Jackson AC, Bjorgan K, During MJ, Sprengel R, Seeburg PH, Nicoll RA (2009) Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62(2):254–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Middei S, Houeland G, Cavallucci V, Ammassari-Teule M, D’Amelio M, Marie H (2013) CREB is necessary for synaptic maintenance and learning-induced changes of the ampa receptor GluA1 subunit. Hippocampus. doi:10.1002/hipo.22108

    PubMed  Google Scholar 

  • Morelli S, Piscioneri A, Salerno S, Rende M, Campana C, Tasselli F, Di Vito A, Giusi G, Canonaco M, Drioli E, De Bartolo L (2012) Flat and tubular membrane systems for the reconstruction of hippocampal neuronal network. J Tissue Eng Regen Med 6(4):299–313

    Article  CAS  PubMed  Google Scholar 

  • Mori H, Mishina M (1995) Structure and function of the NMDA receptor channel. Neuropharmacology 34(10):1219–1237

    Article  CAS  PubMed  Google Scholar 

  • Morikawa E, Mori H, Kiyama Y, Mishina M, Asano T, Kirino T (1998) Attenuation of focal ischemic brain injury in mice deficient in the epsilon1 (NR2A) subunit of NMDA receptor. J Neurosci 18:9727–9732

    CAS  PubMed  Google Scholar 

  • Moutin E, Raynaud F, Roger J, Pellegrino E, Homburger V, Bertaso F, Ollendorff V, Bockaert J, Fagni L, Perroy J (2012) Dynamic remodeling of scaffold interactions in dendritic spines controls synaptic excitability. J Cell Biol 198(2):251–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noh KM, Hwang JY, Follenzi A, Athanasiadou R, Miyawaki T, Greally JM, Bennett MV, Zukin RS (2012) Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci USA 109(16):E962–E971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olney JW, Sharpe LG, Feigin RD (1972) Glutamate-induced brain damage in infant primates. J Neuropathol Exp Neurol 31(3):464–488

    Article  CAS  PubMed  Google Scholar 

  • Petralia RS (2012) Distribution of extrasynaptic NMDA receptors on neurons. Sci World J 2012:267120

    Article  Google Scholar 

  • Pfaffl MW (2004) Quantification strategies in real-time PCR. In: Bustin SA (ed) A-Z of quantitative PCR. International University Line, La Jolla, pp 89–113

    Google Scholar 

  • Pozo K, Goda Y (2010) Unraveling mechanisms of homeostatic synaptic plasticity. Neuron 66(3):337–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Price DL, Rockenstein E, Ubhi K, Phung V, MacLean-Lewis N, Askay D, Cartier A, Spencer B, Patrick C, Desplats P, Ellisman MH, Masliah E (2010) Alterations in mGluR5 expression and signaling in Lewy body disease and in transgenic models of alpha-synucleinopathy-implications for excitotoxicity. PLoS ONE 5(11):e14020

    Article  PubMed  PubMed Central  Google Scholar 

  • Sarichelou I, Cappuccio I, Ferranti F, Mosillo P, Ciceroni C, Sale P, Stocchi F, Battaglia G, Nicoletti F, Melchiorri D (2008) Metabotropic glutamate receptors regulate differentiation of embryonic stem cells into GABAergic neurons. Cell Death Differ 15(4):700–707

    Article  CAS  PubMed  Google Scholar 

  • She WC, Quairiaux C, Albright MJ, Wang YC, Sanchez DE, Chang PS, Welker E, Lu HC (2009) Roles of mGluR5 in synaptic function and plasticity of the mouse thalamocortical pathway. Eur J Neurosci 29(7):1379–1396

    Article  PubMed  PubMed Central  Google Scholar 

  • Shorvon SD (2011) The causes of epilepsy: changing concepts of etiology of epilepsy over the past 150 years. Epilepsia 52(6):1033–1044

    Article  PubMed  Google Scholar 

  • Socodato R, Santiago FN, Portugal CC, Domingues AF, Santiago AR, Relvas JB, Ambrosio AF, Paes-de-Carvalho R (2012) Calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors trigger neuronal nitric-oxide synthase activation to promote nerve cell death in an Src kinase-dependent fashion. J Biol Chem 287(46):38680–38694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takagi N, Besshoh S, Morita H, Terao M, Takeo S, Tanonaka K (2010) Metabotropic glutamate mGlu5 receptor-mediated serine phosphorylation of NMDA receptor subunit NR1 in hippocampal CA1 region after transient global ischemia in rats. Eur J Pharmacol 644(1–3):96–100

    Article  CAS  PubMed  Google Scholar 

  • Takagi N, Besshoh S, Marunouchi T, Takeo S, Tanonaka K (2012) Metabotropic glutamate receptor 5 activation enhances tyrosine phosphorylation of the N-methyl-D-aspartate (NMDA) receptor and NMDA-induced cell death in hippocampal cultured neurons. Biol Pharm Bull 35(12):2224–2229

    Article  CAS  PubMed  Google Scholar 

  • Vannucci RC (2000) Hypoxic-ischemic encephalopathy. Am J Perinatol 17(3):113–120

    Article  CAS  PubMed  Google Scholar 

  • Vannucci RC, Connor JR, Mauger DT, Palmer C, Smith MB, Towfighi J, Vannucci SJ (1999) Rat model of perinatal hypoxic-ischemic brain damage. J Neurosci Res 55(2):158–163

    Article  CAS  PubMed  Google Scholar 

  • Vizi ES, Kisfali M, Lőrincz T (2012) Role of nonsynaptic GluN2B-containing NMDA receptors in excitotoxicity: evidence that fluoxetine selectively inhibits these receptors and may have neuroprotective effects. Brain Res Bull S0361–9230(12):00231–00236

    Google Scholar 

  • Voss OP, Milne S, Sharkey J, O’Neill MJ, McCulloch J (2007) Molecular mechanisms of neurite growth with AMPA receptor potentiation. Neuropharmacology 52(2):590–597

    Article  CAS  PubMed  Google Scholar 

  • Wang PY, Petralia RS, Wang YX, Wenthold RJ, Brenowitz SD (2011) Functional NMDA receptors at axonal growth cones of young hippocampal neurons. J Neurosci 31(25):9289–9297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei XW, Yan H, Xu B, Wu YP, Li C, Zhang GY (2012) Neuroprotection of co-activation of GABA receptors by preventing caspase-3 denitrosylation in KA-induced seizures. Brain Res Bull 88(6):617–623

    Article  CAS  PubMed  Google Scholar 

  • Wu LJ, Mellström B, Wang H, Ren M, Domingo S, Kim SS, Li XY, Chen T, Naranjo JR, Zhuo M (2010) DREAM (downstream regulatory element antagonist modulator) contributes to synaptic depression and contextual fear memory. Mol Brain 3(3):1–13

    Google Scholar 

  • Xiao XL, Ma DL, Wu J, Tang FR (2013) Metabotropic glutamate receptor 5 (mGluR5) regulates proliferation and differentiation of neuronal progenitors in the developmental hippocampus. Brain Res 1493:1–12

    Article  CAS  PubMed  Google Scholar 

  • Yoon YJ, White SL, Ni X, Gokin AP, Martin-Caraballo M (2012) Downregulation of GluA2 AMPA receptor subunits reduces the dendritic arborization of developing spinal motoneurons. PLoS ONE 7(11):e49879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang F, Li C, Wang R, Han D, Zhang QG, Zhou C, Yu HM, Zhang GY (2007) Activation of GABA receptors attenuates neuronal apoptosis through inhibiting the tyrosine phosphorylation of NR2A by Src after cerebral ischemia and reperfusion. Neuroscience 150(4):938–949

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Conflict of interest

Dr. Anna Di Vito, Dr. Maria Mele, Dr. Antonella Piscioneri, Dr. Sabrina Morelli, Dr. Loredana De Bartolo, Dr. Tullio Barni, Dr. Rosa Maria Facciolo, Dr. Marcello Canonaco declares no competing financial interests.

Author information

Authors and Affiliations

  1. Molecular Oncology Laboratory, Experimental and Clinical Medicine Department, University Magna Graecia of Catanzaro, 88100, Catanzaro, Italy

    Anna Di Vito & Tullio Barni

  2. Comparative Neuroanatomy Laboratory (DiBEST), University of Calabria, Arcavacata di Rende, 87030, Cosenza, CS, Italy

    Anna Di Vito, Maria Mele, Rosa Maria Facciolo & Marcello Canonaco

  3. Institute of Membrane Technology, National Research Council, Arcavacata di Rende, 87030, Cosenza, CS, Italy

    Antonella Piscioneri, Sabrina Morelli & Loredana De Bartolo

Authors
  1. Anna Di Vito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Mele
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonella Piscioneri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabrina Morelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Loredana De Bartolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tullio Barni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rosa Maria Facciolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marcello Canonaco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Di Vito.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Di Vito, A., Mele, M., Piscioneri, A. et al. Overstimulation of Glutamate Signals Leads to Hippocampal Transcriptional Plasticity in Hamsters. Cell Mol Neurobiol 34, 501–509 (2014). https://doi.org/10.1007/s10571-014-0034-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-014-0034-0

Keywords

Search

Navigation