Activation of metabotropic glutamate receptors prevents neuronal apoptosis in culture

Cultured granule cells grown in serum-containing medium with a 'low K ⁺' concentration (10 mM) underwent apoptosis after maturation for 5 days in vitro (5 DIV), a time that coincides with the developmental decline in the activity of metabotropic glutamate receptors (mGluRs) coupled to polyphosphoinositide hydrolysis. The mGluR agonist (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) prevented the development of low K ⁺-induced apoptosis and the presence of the drug was critical at 6 and 7 DIV, i.e., after the drop of mGluR activity. The neuroprotective action of 1S,3R-ACPD was prevented by the mGluR antagonist (RS)-α-methyl-4-carboxyphenylglycine (MCPG) and was mimicked by N- methyl-D-aspartate or carbamylcholine but not by agonists of the mGluR subtypes negatively linked to adenylyl cyclase. In cultures treated either with Li ⁺-which reduced polyphosphoinositide response to concentrations of glutamate (5 μM) that approximate those physiologically present in the incubation medium-or MCPG, the development of low K ⁺-induced apoptosis already occurred at 4 DIV. Thus, the activation of mGluRs coupled to polyphosphoinositide hydrolysis by endogenous glutamate could contribute to protect cultured granule cells against apoptosis during early stages of maturation.