Channels formed by the TRP family of proteins serve for a variety of physiological functions.Here we report that two members of the TRPC subfamily,TRPC3 or TRPC6,protects cerebellar granule neurons (CGNs) against serum-deprivation (SD)-induced cell death in cultures and promotes CGNs survival in rat brain.In CGN cultures,blocking TRPC channels or down-regulating TRPC3/6 expression suppresses BDNF-mediated protection,BDNF-triggered intracellular Ca2+ elevation and BDNF-induced CREB activation.By contrast,over-expression of TRPC3/6 increases CREB-dependent reporter-gene transcription and prevents SD-induced cell death,and this protection is blocked by the dominant negative form of CREB.Furthermore,down-regulation of TRPC3/6 with RNAi induces CGN apoptosis in neonatal rat cerebellum and this effect is rescued by over-expressing either TRPC3 or TRPC6.Thus,our findings provide in vitro and in vivo evidence for a critical role of TRPC channels in promoting neuronal survival.