Excitotoxic death of retinal neurons in vivo occurs via a non-cell-autonomous mechanism.
The central hypothesis of excitotoxicity is that excessive stimulation of neuronal NMDA-sensitive glutamate receptors is harmful to neurons and contributes to a variety of neurological disorders. Glial cells have been proposed to participate in excitotoxic neuronal loss, but their precise role is defined poorly. In this in vivo study, we show that NMDA induces profound nuclear factor kappaB (NF-kappaB) activation in Müller glia but not in retinal neurons. Intriguingly, NMDA-induced death of retinal neurons is effectively blocked by inhibitors of NF-kappaB activity. We demonstrate that tumor necrosis factor alpha (TNFalpha) protein produced in Müller glial cells via an NMDA-induced NF-kappaB-dependent pathway plays a crucial role in excitotoxic loss of retinal neurons. This cell loss occurs mainly through a TNFalpha-dependent increase in Ca(2+)-permeable AMPA receptors on susceptible neurons. Thus, our data reveal a novel non-cell-autonomous mechanism by which glial cells can profoundly exacerbate neuronal death following excitotoxic injury.
Lebrun-Julien
Frédéric
F
Department of Pathology and Cell Biology and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
Duplan
Laure
L
Pernet
Vincent
V
Osswald
Ingrid
I
Sapieha
Przemyslaw
P
Bourgeois
Philippe
P
Dickson
Kathleen
K
Bowie
Derek
D
Barker
Philip A
PA
Di Polo
Adriana
A
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000633:toxicity; D055351:Retinal Neurons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate