Recent reports have outlined that cerebellar long-term depression requires the activation of subtype 1 metabotropic glutamate receptors, since long-term depression is impaired in subtype 1 metabotropic glutamate receptor (mGluR1) knockout mice. In order to better define the role of mGluR1-activated signal transduction pathways, we attempted to rescue cerebellar long-term depression in mGluR1 knockout mice by direct activation of subsequent intracellular cascades. The present results demonstrate that the inositol-1,4,5-trisphosphate signal transduction pathway remains functional in mGluR1 knockout mice, that calcium release from internal stores evoked by the combined photolytic release of inositol- 1,4,5-trisphosphate/pairing protocol is sufficient to rescue long-term depression in these mutants, and that this long-term depression is sensitive to a protein kinase C inhibitor. Therefore, our results provide compelling evidence that the impairment of long-term depression observed in mGluR1 knockout mice is not a consequence of developmental abnormalities, but is directly due to mGluR1 gene inactivation.