title: Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity.
abstract: 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 (CB(1)) 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.
authors.affiliation: Neuroimmunology Unit, INSPE, Division of Neuroscience, San Raffaele Scientific Institute Via Olgettina 58, 20132 Milan, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Butti
authors.forename: Marco
authors.initials: M
authors.lastname: Bacigaluppi
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Marco
authors.initials: M
authors.lastname: Cambiaghi
authors.forename: Monica
authors.initials: M
authors.lastname: Bari
authors.forename: Arantxa
authors.initials: A
authors.lastname: Cebrian Silla
authors.forename: Elena
authors.initials: E
authors.lastname: Brambilla
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Roberta
authors.initials: R
authors.lastname: De Ceglia
authors.forename: Luis
authors.initials: L
authors.lastname: Teneud
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Luca
authors.initials: L
authors.lastname: Muzio
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Letizia
authors.initials: L
authors.lastname: Leocani
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
mesh_terms: D015761:4-Aminopyridine / Q000037:antagonists & inhibitors; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D063388:Endocannabinoids / Q000096:biosynthesis / Q000378:metabolism; D004827:Epilepsy / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D015774:Ganciclovir; D018698:Glutamic Acid / Q000494:pharmacology / Q000502:physiology*; D020547:Lateral Ventricles / Q000502:physiology* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D015761:4-Aminopyridine; D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D013759:Dronabinol; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists; D015774:Ganciclovir; D018698:Glutamic Acid; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C062018:HU 211; C078814:anandamide