Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor

Brain-derived neurotrophic factor ( BDNF) is known to promote neuronal survival and differentiation(1) and to guide axon extension both in vitro(2,3) and in vivo(4). The BDNF-induced chemoattraction of axonal growth cones requires Ca2+ signalling(3), but how Ca2+ is regulated by BDNF at the growth cone remains largely unclear. Extracellular application of BDNF triggers membrane currents resembling those through TRPC ( transient receptor potential canonical) channels in rat pontine neurons(5) and in Xenopus spinal neurons(6). Here, we report that in cultured cerebellar granule cells, TRPC channels contribute to the BDNF-induced elevation of Ca2+ at the growth cone and are required for BDNF-induced chemo-attractive turning. Several members of the TRPC family are highly expressed in these neurons, and both Ca2+ elevation and growth-cone turning induced by BDNF are abolished by pharmacological inhibition of TRPC channels, overexpression of a dominant-negative form of TRPC3 or TRPC6, or downregulation of TRPC3 expression via short interfering RNA. Thus, TRPC channel activity is essential for nerve-growth-cone guidance by BDNF.