Brain-derived neurotrophic factor (BDNF) has potent actions on hippocampal neurons, but the mechanisms that initiate its effects are poorly understood. We report here that localized BDNF application to apical dendrites of CA1 pyramidal neurons evoked transient elevations in intracellular Ca²⁺ concentration, which are independent of membrane depolarization and activation of NMDA receptors. These Ca²⁺ signals were always associated with I_BDNF, a slow and sustained non-selective cationic current mediated by TRPC3 channels. BDNF-induced Ca²⁺ elevations required functional Trk and IP₃ receptors, full intracellular Ca²⁺ stores as well as extracellular Ca²⁺, suggesting the involvement of TRPC channels. Indeed, the TRPC channel inhibitor SKF-96365 prevented BDNF-induced Ca²⁺ elevations and the associated I_BDNF. Thus, TRPC channels emerge as novel mediators of BDNF-induced intracellular Ca²⁺ elevations associated with sustained cationic membrane currents in hippocampal pyramidal neurons.