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Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity

Erica Butti, Marco Bacigaluppi, Silvia Rossi, Marco Cambiaghi, Monica Bari, Arantxa Cebrian Silla, Elena Brambilla, Alessandra Musella, Roberta De Ceglia, Luis Teneud, Valentina De Chiara, Patrizia D’Adamo, Jose Manuel Garcia-Verdugo, Giancarlo Comi, Luca Muzio, Angelo Quattrini, Letizia Leocani, Mauro Maccarrone, Diego Centonze, Gianvito Martino
DOI: http://dx.doi.org/10.1093/brain/aws194 3320-3335 First published online: 24 September 2012

Summary

The functional significance of adult neural stem and progenitor cells in hippocampal-dependent learning and memory has been well documented. Although adult neural stem and progenitor cells in the subventricular zone are known to migrate to, maintain and reorganize the olfactory bulb, it is less clear whether they are functionally required for other processes. Using a conditional transgenic mouse model, selective ablation of adult neural stem and progenitor cells in the subventricular zone induced a dramatic increase in morbidity and mortality of central nervous system disorders characterized by excitotoxicity-induced cell death accompanied by reactive inflammation, such as 4-aminopyridine-induced epilepsy and ischaemic stroke. To test the role of subventricular zone adult neural stem and progenitor cells in protecting central nervous system tissue from glutamatergic excitotoxicity, neurophysiological recordings of spontaneous excitatory postsynaptic currents from single medium spiny striatal neurons were measured on acute brain slices. Indeed, lipopolysaccharide-stimulated, but not unstimulated, subventricular zone adult neural stem and progenitor cells reverted the increased frequency and duration of spontaneous excitatory postsynaptic currents by secreting the endocannabinod arachidonoyl ethanolamide, a molecule that regulates glutamatergic tone through type 1 cannabinoid receptor (CB1) binding. In vivo restoration of cannabinoid levels, either by administration of the type 1 cannabinoid receptor agonist HU210 or the inhibitor of the principal catabolic enzyme fatty acid amide hydrolase, URB597, completely reverted the increased morbidity and mortality of adult neural stem and progenitor cell-ablated mice suffering from epilepsy and ischaemic stroke. Our results provide the first evidence that adult neural stem and progenitor cells located within the subventricular zone exert an ‘innate’ homeostatic regulatory role by protecting striatal neurons from glutamate-mediated excitotoxicity.

  • neurogenesis
  • ischaemia
  • neural stem cells
  • excitotoxicity
  • endocannabinoids
  • Abbreviations
    AEA
    arachidonoyl ethanolamide
    AraC
    cytosine β-d-arabinofuranoside hydrochloride
    EPSC
    excitatory post-synaptic current
    GCV
    ganciclovir
    LC–ESI–MS
    liquid chromatography–electrospray ionization mass spectrometry
    MCAO
    middle cerebral artery occlusion
    NBQX
    2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione
    NPCs
    neural stem/progenitor cells
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