TY  - JOUR
VL  - 25
Y1  - 2005/03/16/
TI  - Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived fas ligand
IS  - 11
A1  - Taylor, DL
A1  - Jones, F
A1  - Kubota, ESFCS
A1  - Pocock, JM
KW  - metabotropic glutamate receptor
KW  -  neurodegenerative disease
KW  -  microglia
KW  -  neuroprotection
KW  -  TNF alpha
KW  -  FasL
KW  -  CEREBELLAR GRANULE CELLS
KW  -  METHYL-D-ASPARTATE
KW  -  CHROMOGRANIN-A
KW  -  TNF-ALPHA
KW  -  INDUCED APOPTOSIS
KW  -  IN-VITRO
KW  -  ACTIVATED MICROGLIA
KW  -  SIGNAL-TRANSDUCTION
KW  -  ALZHEIMERS-DISEASE
KW  -  MEDIATED APOPTOSIS
EP  -  2964
JF  - J NEUROSCI
PB  - SOC NEUROSCIENCE
ID  - discovery7725
UR  - https://discovery.ucl.ac.uk/id/eprint/7725/
AV  - public
SN  - 0270-6474
N2  - Activated microglia may be detrimental to neuronal survival in a number of neurodegenerative diseases. Thus, strategies that reduce microglial neurotoxicity may have therapeutic benefit. Stimulation of group II metabotropic glutamate (mGlu) receptors on rat primary microglia with the specific group II agonist 2S, 2 ' R, 3 ' R- 2-(2 ', 3 '-dicarboxy-cyclopropyl) glycine for 24 h induced microglial activation and resulted in a neurotoxic microglial phenotype. These effects were attributable to preferential mGlu2 stimulation, because N-acetyl-L-aspartyl-L-glutamate, a specific mGlu3 agonist, did not induce microglial activation or neurotoxicity. Stimulation of microglial mGlu2 but not mGlu3 induced caspase-3 activation in cerebellar granule neurons in culture, using microglial-conditioned media as well as cocultures. Stimulation of microglial mGlu2 induced tumor necrosis factor-alpha(TNF alpha) release, which contributed to microglial neurotoxicity mediated via neuronal TNF receptor 1 and caspase-3 activation. Stimulation of microglial group I or III mGlu receptors did not induce TNF alpha release. TNF alpha was only neurotoxic in the presence of microglia or microglial-conditioned medium. The toxicity of TNF alpha could be prevented by coexposure of neurons to conditioned medium from microglia stimulated by the specific group III agonist L-2-amino-4-phosphono-butyric acid. The neurotoxicity of TNF alpha derived from mGlu2-stimulated microglia was potentiated by microglial-derived Fas ligand (FasL), the death receptor ligand. FasL was constitutively expressed in microglia and shed after mGlu2 stimulation. Our data suggest that selective and inverse modulation of microglial mGlu2 and mGlu3 may prove a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease and multiple sclerosis.
SP  - 2952 
ER  -