Neurotrophic factors and synaptic plasticity

Models of activity-dependent synaptic plasticity, whether in the context of development or of learning and memory, have long postulated the existence of extracellular signal-ing molecules that enhance and stabilize active synapses. In recent years, neurotrophic factors have emerged as attractive candidates for such signaling molecules. The work of several laboratories has shown that neurotrophins fulfill the two major criteria for any such mediators of syn-aptic plasticity: their production is regulated by neuronal activity, and neurotrophic factors, in turn, have potent effects on the signaling properties of target neurons. Neuro-trophic factors represent a new and exciting class of molecules for a signaling role in synaptic plasticity because of their strong regulation of gene expression and neuronal morphology; neurotrophic factors could consequently regulate neuronal excitability and synaptic function over a much longer time scale than conventional neuromodulators. The neurotrophic factors that have been most studied in this regard are the neurotrophins, which are much better known for their promotion of neuronal survival and differentiation. Nerve growth factor (NGF) remains the arche-typical neurotrophin; in addition, the neurotrophin family now includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, and NT-6 (reviewed in Lind-say et al., 1994; GOtz et al., 1994). Responsiveness to particular neurotrophins is mediated through receptors specific for each factor. These receptors, members of the trk family of protooncogenes, are receptor tyrosine ki-nases related to other peptide factor receptors such as insulin and epidermal growth factor (EGF) receptors. Although cross-activation can occur, in neurons TrkA is primarily a receptor for NGF, TrkB a receptor for BDNF and NT-4/5, and TrkC a receptor for NT-3. Regulation of neurotrophin mRNA levels by activity was first discovered in the hippocampus, where high basal levels of neurotrophins are expressed. NGF and BDNF mRNA levels, but not those for NT-3, are rapidly and strongly regulated by epileptiform activity in the hippocam-pus; even a single epileptiform afterdischarge is sufficient to increase levels of NGF and BDNF mRNA substantially (e.g., Ernfors et al., 1991; Isackson et al., 1991). Changes in BDNF mRNA levels are particularly dramatic, increasing by over 6-fold in dentate granule cells within 30 min after stimulation of seizure activity (Ernfors et al., 1991). These increases in NGF and BDNF mRNAs are transient, returning to control levels after 24 hr (Isackson et al., 1991 ; Ernfors et al., 1991). Importantly, conditions inducing long-term potentiation (LTP) in the hippocampus have also been shown to increase BDNF and NT-3 …