Temporal lobe epilepsy (TLE) is the most common form of intractable epilepsy and is always accompanied with hippocampal sclerosis. The molecular mechanism of this pathological phenomenon has been extensively explored, yet remains unclear. Previous studies suggest that ion channels, especially calcium channels, might play important roles. Transient receptor potential canonical channel (TRPC) is a novel cation channel dominantly permeable to Ca(2+) and widely expressed in the human brain. We measured the expression of two subtypes of TRPC channels, TRPC3 and TRPC6, in temporal lobe epileptic foci excised from patients with intractable epilepsy and in hippocampus of mice with pilocarpine-induced status epilepticus (SE), an animal model of TLE. Cortical TRPC3 and TRPC6 protein expressions were significantly higher in TLE patients compared with those in controls. Expression of TRPC3 and TRPC6 protein also increased significantly in the CA3 region of the hippocampus of SE mice. Inhibition of TRPC3 by intracerebroventricular injection of anti-TRPC3 antibody prevented aberrant-sprouted mossy fiber collaterals in the CA3 region, while inhibition of TRPC6 by anti-TRPC6 antibody reduced dendritic arborization and spine density of CA3 pyramidal neurons. Our results indicate that TRPC3 and TRPC6 participate diversely in synaptic reorganization in the mossy fiber pathway in TLE.