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 d ays in vitro (5 DIV), a time that coincides with the developmental dec line in the activity of metabotropic glutamate receptors (mGluRs) coup led to polyphosphoinositide hydrolysis. The mGluR agonist (1S,3R)-1-am inocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) prevented the devel opment of low K+-induced apoptosis and the presence of the drug was cr itical at 6 and 7 DIV, i.e., after the drop of mGluR activity. The neu roprotective action of 1S,3R-ACPD was prevented by the mGluR antagonis t (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) and was mimicked by N-methyl-D-aspartate or carbamylcholine but not by agonists of the mGl uR subtypes negatively linked to adenylyl cyclase. In cultures treated either with Li+-which reduced polyphosphoinositide response to concen trations of glutamate (5 mu M) that approximate those physiologically present in the incubation medium-or MCPG, the development of low K+-in duced apoptosis already occurred at 4 DIV. Thus, the activation of mGl uRs coupled to polyphosphoinositide hydrolysis by endogenous glutamate could contribute to protect cultured granule cells against apoptosis during early stages of maturation.