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The Journal of Neuroscience, March 18, 2009, 29(11):3442-3452; doi:10.1523/JNEUROSCI.5804-08.2009

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Neurobiology of Disease
Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Diego Centonze,^1,2 * Luca Muzio,^5 * Silvia Rossi,^1,2 Francesca Cavasinni,⁵ Valentina De Chiara,^1,2 Alessandra Bergami,⁵ Alessandra Musella,^1,2 Marcello D'Amelio,³ Virve Cavallucci,³ Alessandro Martorana,¹ Andrea Bergamaschi,⁵ Maria Teresa Cencioni,⁴ Adamo Diamantini,⁴ Erica Butti,⁵ Giancarlo Comi,⁵ Giorgio Bernardi,^1,2 Francesco Cecconi,³ Luca Battistini,⁴ Roberto Furlan,⁵ and Gianvito Martino⁵

¹Neurologic Clinic, Department of Neuroscience, Tor Vergata University, 00133 Rome, Italy, ²Laboratory of Experimental Neurology, ³Laboratory of Molecular Neuroembryology, and ⁴Neuroimmunology Unit, Santa Lucia Foundation at the Centro Europeo per la Ricerca sul Cervello, 00143 Rome, Italy, and ⁵Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy

Correspondence should be addressed to either of the following: Diego Centonze, Neurologic Clinic, Department of Neuroscience, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy, Email: centonze{at}uniroma2.it; or Gianvito Martino, Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy, Email: martino.gianvito{at}hsr.it

Neurodegeneration is the irremediable pathological event occurring during chronic inflammatory diseases of the CNS. Here we show that, in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, inflammation is capable in enhancing glutamate transmission in the striatum and in promoting synaptic degeneration and dendritic spine loss. These alterations occur early in the disease course, are independent of demyelination, and are strongly associated with massive release of tumor necrosis factor- from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early gene Arc/Arg3.1, leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced synaptopathy subsided during pharmacological blockade of AMPA receptors. Our data establish a link between neuroinflammation and synaptic degeneration and calls for early neuroprotective therapies in chronic inflammatory diseases of the CNS.

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Received Dec. 5, 2008; revised Feb. 4, 2009; accepted Feb. 8, 2009.

Correspondence should be addressed to either of the following: Diego Centonze, Neurologic Clinic, Department of Neuroscience, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy, Email: centonze{at}uniroma2.it; or Gianvito Martino, Neuroimmunology Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy, Email: martino.gianvito{at}hsr.it

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