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

Chiara Cervetto, Laura Vergani, Mario Passalacqua, Milena Ragazzoni, Arianna Venturini, Francesco Cecconi, Nicola Berretta, Nicola Mercuri, Marcello D’Amelio, Guido Maura, Paolo Mariottini, Adriana Voci, Manuela Marcoli, Manuela Cervelli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)50-68
Number of pages19
JournalNeuroMolecular Medicine
Volume18
Issue number1
DOIs
Publication statusE-pub ahead of print - Nov 3 2015

Keywords

  • Astrocyte processes
  • Cerebral cortex
  • Epileptic-like activity
  • Excitotoxicity
  • Glutamate release
  • Kainate
  • Metallothioneins
  • Oxidative stress
  • Polyamines
  • Spermine oxidase

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Medicine
  • Neurology

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  • Cite this

    Cervetto, C., Vergani, L., Passalacqua, M., Ragazzoni, M., Venturini, A., Cecconi, F., Berretta, N., Mercuri, N., D’Amelio, M., Maura, G., Mariottini, P., Voci, A., Marcoli, M., & Cervelli, M. (2015). Astrocyte-Dependent Vulnerability to Excitotoxicity in Spermine Oxidase-Overexpressing Mouse. NeuroMolecular Medicine, 18(1), 50-68. https://doi.org/10.1007/s12017-015-8377-3