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Transient Receptor Potential Canonical 3 (TRPC3) channels have been demonstrated to underlie a slow excitatory postsynaptic current (sEPSC) that is coupled to the activation of type-1 metabotropic glutamate receptor (mGluR1) by glutamate release at the parallel fiber -Purkinje cell synapses of the cerebellum. On the other hand, Purkinje neurons receive extensive inhibitory synaptic inputs from interneurons located in the molecular layer of cerebellar cortex and GABA B receptors (GABA B Rs) are expressed on the dendrites of Purkinje cells and often co-localized with mGluR1. It has been shown that activation of postsynaptic GABA B Rs potentiates mGluR1-coupled sEPSCs in Purkinje cells, but the underlying molecular mechanism remains elusive. Here we report that the potentiation of mGluR1-coupled sEPSCs in Purkinje cells by stimulating postsynaptic GABA B Rs was completely absent in TRPC3 knockout mice, but persistent in TRPC1-, TRPC4-and TRPC1/4/5/6knockout mice, suggesting that TRPC3 is the only TRPC isoform that mediates the potentiation. Moreover, our results indicate that the potentiation was a pure postsynaptic event because it was not affected by blocking neurotransmission with tetrodotoxin. Furthermore, we found that the potentiation was blocked by antagonists of either GABA B Rs or mGluR1, suggesting that it may originate directly from the integration of synaptic signals at the receptor level and the strengthened signal was mainly mediated by mGluR1-TRPC3 coupling instead of any other pathways involved in GABA B R signaling. Since mGluR1-TRPC3 coupling is essential in cerebellar long-term depression, synapse elimination, and motor coordination, our findings that TRPC3 is also responsible for the synaptic integration of GABA B R-mediated inputs may suggest a novel mechanism that underlies essential cerebellar functions, such as motor learning.

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