Neurotrophins and their receptors: A convergence point for many signalling pathways

Key Points Neurotrophins are most often associated with the promotion of neuronal growth and survival, but their influence on brain function is significantly broader — they are also involved in plastic and pathological processes. Clues to the multiple functions of neurotrophins come from the study of mutant animals. In particular, as knocking out any neurotrophin gene leads to a lethal phenotype, the analysis of heterozygous mice has pointed to roles for the neurotrophins in locomotor and feeding behaviours. The fact that the actions of the neurotrophins depend on two receptor classes — the Trk receptors and p75 — significantly increases the degrees of freedom for neurotrophin signalling in terms of specificity, affinity and downstream signalling pathways. Neurotrophins have significant direct effects on synaptic transmission, plasticity and their possible behavioural correlates. However, the downstream mechanisms that mediate these effects are not completely understood. Several signalling pathways have been put forward as candidates, and recently ion channels have joined the list of potential effectors of the synaptic actions of neurotrophins. Transactivation of neurotrophin receptors by G protein-coupled receptors has emerged as a new theme in the biology of neurotrophin function. Although the precise role of this transactivation is unknown, one possibility is that it adds a safety factor that might protect neurons from death in the absence of neurotrophins. Neurotrophin receptors, particularly p75, might have an important role in the control of axonal regeneration, as they act as co-receptors for Nogo, a protein that is known to inhibit axonal growth. In addition, the neurotrophins can modulate the response of growth cones to guidance molecules such as semaphorins. There is some genetic evidence that points to a specific contribution of the neurotrophins to psychiatric disease. Specifically, polymorphisms of brain-derived neurotrophic factor have been linked to depression, bipolar disorders and schizophrenia. The neurotrophins are a family of proteins that are essential for the development of the vertebrate nervous system. Each neurotrophin can signal through two different types of cell surface receptor — the Trk receptor tyrosine kinases and the p75 neurotrophin receptor. Given the wide range of activities that are now associated with neurotrophins, it is probable that additional regulatory events and signalling systems are involved. Here, I review rec