A variety of extracellular signals are transduced across the cell membrane by the enzyme phosphoinositide-specific phospholipase C-beta (PLC-beta) coupled with guanine-nucleotide-binding G proteins’. There are four isoenzymes of PLC-beta, beta 1-beta 4, but their functions in vivo are not known. Here we investigate the role of PLC-beta 1 and PLC-beta 4 in the brain by generating-null mutations in mice : we found that PLC beta 1(-/-) mice developed epilepsy and PLC beta 4(-/-) mice showed ataxia. We determined the molecular basis of these phenotypes and show that PLC-beta 1 is involved in signal transduction in the cerebral cortex and hippocampus by coupling pre-dominantly to the muscarinic acetylcholine receptor, whereas PLC-beta 4 works through the metabotropic glutamate receptor in the cerebellum, illustrating how PLC-beta isoenzymes are used to generate different functions in the brain.