TRPC3 channel underlies cerebellar long-term depression.

Cerebellar long-term depression (LTD) is induced by repetitive pairing of both synaptic inputs provided by climbing fibers (CFs) and parallel fibers (PFs), especially when CF stimulation followed by burst of PFs. Metabotropic glutamate receptor type 1 (mGluR1)-dependent signaling in Purkinje cells is critically involved in the induction of cerebellar LTD. Signaling pathway of mGluR1 has two limbs: one is IP3 receptor-mediated Ca release from intracellular Ca store and the other is activation of transient receptor potential canonical (TRPC) channels. Here, we hypothesized that TRPC3, which is reported to be responsible for mGluR1-evoked slow currents, mediates the induction of the cerebellar LTD. Purkinje cells were loaded with antibodies which act against a cytoplasmic epitope of TRPC3 channels, acting as a specific antagonist of TRPC3. About 30 min after achieving a whole-cell configuration, mGluR1-evoked slow currents were significantly reduced; a possible cause of this time delay might be the diffusion time course from patch pipette to the dendrite site of mGluR1 activation. Taking this delay into consideration, we next attempted to induce cerebellar LTD by pairing PFs and CF. It was found that cerebellar LTD was hindered in the presence of TRPC3 antibodies. Taken together, our data suggest that TRPC3 activation may be essential for the induction of LTD in cerebellar Purkinje cells.