Mechanism of neurotrophin-evoked neuronal signalling

Arthur Konnerth, Institute of Physiology, Ludwig-Maximilians University Munich, Germany

Brain-derived neurotrophic factor (BDNF) and other neurotrophins are essential for the normal function of the mammalian nervous system. A rapid, transmitter-like neuroexcitatory action of BDNF is found in many types of central neurons. There is accumulating evidence that this action of BDNF plays important roles in neuronal (and glial!) signalling and in activity-dependent synaptic plasticity. For example, by imaging dentate granule cells in mouse hippocampal slices, we found that pulse-like BDNF applications evoke Ca²⁺ transients, which are associated with the previously reported rapid depolarisation (Kafitz et al., 1998). The BDNF-evoked response was reliably obtained in the cell’s soma and in dendrites, but not in the axon. Particularly large Ca²⁺ signals were detected in dendritic spines. Pairing a weak burst of synaptic stimulation with a brief dendritic BDNF application caused an immediate and robust induction of long-term potentiation (LTP) (Kovalchuk et al., 2002). The LTP induction process involved activation of both postsynaptic Ca²⁺ channels and NMDA receptors. We conclude that spiny dendrites of mature dentate granule cells are highly responsive compartments for the rapid BDNF-action. The findings indicate a surprisingly fast and instructive role for BDNF in the induction of LTP. By screening candidate genes with an antisense mRNA expression approach and by co-expressing the receptor tyrosine kinase TrkB and various sodium channels, we found that the tetrodotoxin-insensitive sodium channel Na_v1.9 underlies the neurotrophin-evoked excitation (Blum et al., 2002). These results clarify the molecular basis of neurotrophin-evoked depolarisation and reveal a novel mechanism of ligand-mediated sodium channel activation.