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

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 recent findings that neurotrophins, in addition to promoting survival and differentiation, exert various effects through

surprising interactions with other receptors and ion channels.

Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, 10016, New York, USA

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the

amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike. LTP is most often studied in the hippocampus and is often considered to be the

cellular basis of learning and memory in vertebrates.

The process of programmed cell death, characterized by distinctive morphological changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic

cleavage of genomic DNA.

This test depends on the natural tendency of rodents to explore the environment in the absence of a threat and to retreat to an enclosed area when fearful. The animals are placed in an

apparatus that has a dark and an illuminated compartment. Reduced exploration of the bright compartment and a reduced number of transitions between compartments are commonly interpreted as

measures of anxiety.

An endopeptidase with specificity for the consensus sequence Arg-X-Lys/Arg-Arg.

An experimental model of epilepsy in which an increased susceptibility to seizures arises after daily focal stimulation of specific brain areas (for example, the amygdala) — stimulation that

does not reach the threshold to elicit a seizure by itself.

A mutation that can be selectively targeted to specific organs (or cell types within an organ) or induced at a specific developmental stage.

The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.

A commonly used model of depression in which animals are exposed to inescapable shock and subsequently tested for deficits in learning a shock-avoidance task. Learned helplessness is a rare

example in which, rather than working from the psychiatric disorder to the model, the behavioural effect was originally discovered in experimental animals (dogs) and later invoked to explain

depression.

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