Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis.
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-alpha 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.
Centonze
Diego
D
Neurologic Clinic, Department of Neuroscience, Tor Vergata University, 00133 Rome, Italy. centonze@uniroma2.it
Muzio
Luca
L
Rossi
Silvia
S
Cavasinni
Francesca
F
De Chiara
Valentina
V
Bergami
Alessandra
A
Musella
Alessandra
A
D'Amelio
Marcello
M
Cavallucci
Virve
V
Martorana
Alessandro
A
Bergamaschi
Andrea
A
Cencioni
Maria Teresa
MT
Diamantini
Adamo
A
Butti
Erica
E
Comi
Giancarlo
G
Bernardi
Giorgio
G
Cecconi
Francesco
F
Battistini
Luca
L
Furlan
Roberto
R
Martino
Gianvito
G
D000818:Animals; D002461:Cell Line, Transformed; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
D018091:Receptors, AMPA