Regulation of Neurotrophin Signaling by Neuronal Activity

The neurotrophic functions of neurotrophins depend in large part on a cytoplasmic signal-transduction cascade, whose efficacy may be influenced by the presence of electrical activity in the neuron. Seizure activity, as well as nonseizure activity of a frequency or intensity capable of inducing LTP, has been shown to elevate BDNF mRNA levels and to facilitate the release of BDNF from hippocampal and cortical neurons (Poo 2001). Although BDNF was originally considered to be transported only retrogradely, evidence indicates that BDNF can also act anterogradely to modulate synaptic plasticity (Poo 2001). High-frequency neuronal activity and synaptic transmission have also been shown to elevate the number of TrkB receptors on the surface of cultured hippocampal neurons through activation of the CaMKII pathway and may therefore facilitate the synaptic action of BDNF (Du et al. 2000). Thus, electrically active nerve terminals may be more susceptible to synaptic potentiation by secreted neurotrophins than are inactive terminals. Neuronal or synaptic activity is also known to promote the effects of neurotrophins on the survival of cultured retinal ganglion cells; here, neuronal or synaptic activity elevates cAMP levels to enhance the responsiveness of the neuron to neurotrophins, apparently by recruiting extra TrkB receptors to the plasma membrane (Meyer-Franke et al. 1998). Moreover, the internalization of BDNF receptor TrkB is also upregulated by activity as a retrograde signal to the cell body in cultured hippocampal neurons (this regulation is discussed in some detail in Du et al. 2003). The activity-dependent regulation of BDNF signaling on BDNF synthesis and release, TrkB insertion onto neuronal surfaces, and activated TrkB tyrosine kinase internalization are crucial for its influence on synaptic plasticity and neuronal survival.

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