THE METABOTROPIC GLUTAMATE-RECEPTOR MGLU5 CONTROLS THE ONSET OF DEVELOPMENTAL APOPTOSIS IN CULTURED CEREBELLAR NEURONS

Cultured cerebellar granule cells grown in medium containing 10 mM Kundergo apoptosis after 4-5 days in vitro (DIV), and, at that time, th e activity of metabotropic glutamate (mGlu) receptors coupled to polyp hosphoinositide (PI) hydrolysis begins to decline. In granule cells at 4 DIV, the mGlu receptor subtype mGlu5 was expressed at high levels. The expression of another PI-coupled mGlu receptor, the mGlu1a, was lo w at 4 DIV but increased during the following days. In cultures at 4-5 DIV, the few cells that already showed an apoptotic phenotype were de void of mGlu5 receptors, but they all expressed mGlu1a receptors. The development of apoptosis was accelerated after treating the cultures w ith: (i) mGlu5 antisense oligonucleotides; (ii) the mixed mGlu recepto r antagonist, (+)-alpha-methyl-4-carboxyphenylglycine; or (iii) the gl utamate depleting enzyme, alanine aminotransferase. In contrast, an in duced overexpression of mGlu5 receptors protected cultured granule cel ls against apoptotic death. We suggest that the activity of mGlu5 rece ptors supports cell survival, and a decline in the expression of mGlu5 receptors gives access to programmed cell death in cerebellar granule cells developing in primary cultures.