Journal Article

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

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

2016

Overview

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 Ca 2+ -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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Animals / Aspartic Acid - metabolism / Astrocytes - drug effects / Astrocytes - pathology / Benzodiazepines - pharmacology / Biogenic Polyamines - metabolism / Biomedical and Life Sciences / Biomedicine / Calcium - metabolism / Cerebral Cortex - enzymology / Cerebral Cortex - pathology / Cerebral Cortex - physiopathology / Enzyme Induction / Genetic Predisposition to Disease / Gliosis - genetics / Hippocampus - enzymology / Hippocampus - pathology / Hippocampus - physiopathology / Internal Medicine / Kainic Acid - pharmacology / Male / Metallothionein - physiology / Mice / Mice, Neurologic Mutants / Mice, Transgenic / Nerve Tissue Proteins - biosynthesis / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - physiology / Neurology / Neurons - pathology / Neurosciences / Neurotoxins - pharmacology / Original Paper / Oxidative Stress / Oxidoreductases Acting on CH-NH Group Donors - biosynthesis / Oxidoreductases Acting on CH-NH Group Donors - genetics / Oxidoreductases Acting on CH-NH Group Donors - physiology / Polyamine Oxidase / Receptors, AMPA - drug effects / Receptors, AMPA - physiology / Recombinant Fusion Proteins - biosynthesis / Seizures - chemically induced / Seizures - genetics / Seizures - physiopathology / Synaptosomes - drug effects / Synaptosomes - physiology / Up-Regulation