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Astrocyte-Dependent Vulnerability to Excitotoxicity in Spermine Oxidase-Overexpressing Mouse

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Abstract

Transgenic mice overexpressing spermine oxidase (SMO) in the cerebral cortex (Dach-SMO mice) showed increased vulnerability to excitotoxic brain injury and kainate-induced epileptic seizures. To investigate the mechanisms by which SMO overexpression leads to increased susceptibility to kainate excitotoxicity and seizure, in the cerebral cortex of Dach-SMO and control mice we assessed markers for astrocyte proliferation and neuron loss, and the ability of kainate to evoke glutamate release from nerve terminals and astrocyte processes. Moreover, we assessed a possible role of astrocytes in an in vitro model of epileptic-like activity in combined cortico-hippocampal slices recorded with a multi-electrode array device. In parallel, as the brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms, we analyzed the oxidative status of the cerebral cortex of both SMO-overexpressing and control mice by evaluating enzymatic and non-enzymatic scavengers such as metallothioneins. The main findings in the cerebral cortex of Dach-SMO mice as compared to controls are the following: astrocyte activation and neuron loss; increased oxidative stress and activation of defense mechanisms involving both neurons and astrocytes; increased susceptibility to kainate-evoked cortical epileptogenic activity, dependent on astrocyte function; appearance of a glutamate-releasing response to kainate from astrocyte processes due to activation of Ca2+-permeable AMPA receptors in Dach-SMO mice. We conclude that reactive astrocytosis and activation of glutamate release from astrocyte processes might contribute, together with increased reactive oxygen species production, to the vulnerability to kainate excitotoxicity in Dach-SMO mice. This mouse model with a deregulated polyamine metabolism would shed light on roles for astrocytes in increasing vulnerability to excitotoxic neuron injury.

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Acknowledgments

C.C. and M.M. thank the University of Genova for financial support; M.C. and P.M. wish to thank the University of Roma Tre for financial support. The authors acknowledge the excellent service of the mouse facility, University of Tor Vergata, Rome (I).

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Authors and Affiliations

  1. Section of Pharmacology and Toxicology, Department of Pharmacy, University of Genova, Viale Cembrano 4, 16148, Genoa, Italy

    Chiara Cervetto, Arianna Venturini, Guido Maura & Manuela Marcoli

  2. Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 5, 16132, Genoa, Italy

    Chiara Cervetto, Guido Maura & Manuela Marcoli

  3. Department of Earth, Environment and Life Sciences (DISTAV), University of Genova, Corso Europa 26, 16132, Genoa, Italy

    Laura Vergani, Milena Ragazzoni & Adriana Voci

  4. Department of Experimental Medicine, University of Genova, Via L. B. Alberti 2, 16132, Genoa, Italy

    Mario Passalacqua

  5. Department of Biology, University of Rome ‘Tor Vergata’, Via della Ricerca Scientifica, 00133, Rome, Italy

    Francesco Cecconi

  6. Department of Experimental Neurosciences, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143, Rome, Italy

    Francesco Cecconi, Nicola Berretta, Nicola Mercuri & Marcello D’Amelio

  7. Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark

    Francesco Cecconi

  8. Department of Systems Medicine, University of Rome ‘Tor Vergata’, Viale Oxford 81, 00133, Rome, Italy

    Nicola Mercuri

  9. Medical School Campus, Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy

    Marcello D’Amelio

  10. Department of Sciences, University of Rome “Roma Tre”, Viale Marconi 446, 00146, Rome, Italy

    Paolo Mariottini & Manuela Cervelli

  11. Interuniversity Consortium of Structural and Systems Biology, Viale Medaglie d’Oro 305, 00136, Rome, Italy

    Paolo Mariottini & Manuela Cervelli

Authors
  1. Chiara Cervetto
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  2. Laura Vergani
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  3. Mario Passalacqua
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  4. Milena Ragazzoni
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  5. Arianna Venturini
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  6. Francesco Cecconi
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  7. Nicola Berretta
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  8. Nicola Mercuri
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  9. Marcello D’Amelio
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  10. Guido Maura
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  11. Paolo Mariottini
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  12. Adriana Voci
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  13. Manuela Marcoli
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  14. Manuela Cervelli
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Corresponding authors

Correspondence to Manuela Marcoli or Manuela Cervelli.

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Cervetto, C., Vergani, L., Passalacqua, M. et al. Astrocyte-Dependent Vulnerability to Excitotoxicity in Spermine Oxidase-Overexpressing Mouse. Neuromol Med 18, 50–68 (2016). https://doi.org/10.1007/s12017-015-8377-3

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  • DOI: https://doi.org/10.1007/s12017-015-8377-3

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