Expression and signaling of group I metabotropic glutamate receptors in astrocytes and microglia

Stimulation of astrocytes with the excitatory neurotransmitter glutamate leads to the formation of inositol 1,4,5-trisphosphate and the subsequent increase of intracellular calcium content. Astrocytes express both ionotropic receptors and metabotropic glutamate (mGlu) receptors, of which mGlu₅ receptors are probably involved in glutamate-induced calcium signaling. The mGlu₅ receptor occurs as two splice variants, mGlu(5a) and mGlu(5b), but it was hitherto unknown which splice variant is responsible for the glutamate- induced effects in astrocytes. We report here that both mRNAs encoding mGlu₅ receptor splice variants are expressed by cultured astrocytes. The expression of mGlu(5a) receptor mRNA is much stronger than that of mGlu(5b) receptor mRNA in these cells. In situ hybridization experiments reveal neuronal expression of mGlu(5b) receptor mRNA in adult rat forebrain but a strong neuronal expression of mGlu(5a) mRNA only in olfactory bulb. Signals for mGlu(5a) receptor mRNA in the rest of the brain were diffuse and weak but consistently above background. Activation of mGlu₅ receptors in astrocytes yields increases in inositol phosphate production and transient calcium responses. It is surprising that the rank order of agonist potency [quisqualate > (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine = trans-(1S,3R)-1- amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD) > glutamate] differs from that reported for recombinantly expressed mGlu(5a) receptors. The expression of mGlu(5a) receptor mRNA and the occurrence of 1S,3R-ACPD- induced calcium signaling were found also in cultured microglia, indicating for the first time expression of mGlu(5a) receptors in these macrophage-like cells.