Activation of microglial group III mGlu receptors inhibits the release of soluble, stable neurotoxins. Activation of microglial group III mGlu receptors inhibits the release of soluble, stable neurotoxins. Neuronal apoptosis was measured with Hoechst 33342 staining after 24 hr microglial–neuronal coculture. Microglia without stimulation in coculture with neurons (control) did not induce apoptosis above that in primary cultures of cerebellar granule neurons cultured alone (neurons alone). Addition of CGA (50 nm) produced significantly elevated levels of neuronal apoptosis when compared with control. The group III mGlu receptor agonists l-AP-4 (100 μm) orRS-PPG (100 μm) significantly reduced CGA evoked apoptosis to levels observed in control. This protection byl-AP-4 or RS-PPG could be attenuated by coexposure of the cocultures with MAP4 (2 mm withl-AP-4 or 500 μm with RS-PPG). Addition of LPS (1 μg/ml) produced significantly elevated levels of neuronal apoptosis when compared with control, which could be attenuated by l-AP-4 or RS-PPG. The neuroprotection afforded by the mGlu receptor agonists could be prevented by coexposure with MAP4. ***Significance levels are shown for comparisons with the apoptosis induced with the microglial activator, e.g., CGA or LPS alone (p < 0.005). Data are the mean ± SEM of at least four determinations. Deanna L. Taylor et al. J. Neurosci. 2003;23:2150-2160 ©2003 by Society for Neuroscience