REVIEWS NEUROTROPHINS AND THEIR RECEPTORS: A CONVERGENCE POINT FOR MANY SIGNALLING PATHWAYS Moses V.Chao 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. 5,6 LONG-TERM POTENTIATION The era of growth factor research began fifty years ago receptor . Despite considerable progress in understand- (LTP).An enduring increase in with the discovery of nerve growth factor (NGF). Since ing the roles of these receptors, additional mechanisms the amplitude of excitatory then, the momentum to study the NGF — or neu- are needed to explain the many cellular and synaptic postsynaptic potentials as a rotrophin — family has never abated because of their interactions that occur between neurons. An emerging result of high-frequency (tetanic) stimulation of afferent continuous capacity to provide new insights into neural view is that neurotrophin receptors act as sensors for var- pathways. It is measured both as function; the influence of neurotrophins spans from ious extracellular and intracellular inputs, and several the amplitude of excitatory developmental neurobiology to neurodegenerative and new mechanisms have recently been put forward. Here, I postsynaptic potentials and as psychiatric disorders. In addition to their classic effects will consider several ways in which Trk and p75 receptors the magnitude of the postsynaptic-cell population on neuronal cell survival, neurotrophins can also regu- might account for the unique effects of neurotrophins spike. LTP is most often studied late axonal and dendritic growth and guidance, synaptic on behaviour and higher-order activities. in the hippocampus and is often structure and connections, neurotransmitter release, considered to be the cellular LONG-TERM POTENTIATION (LTP) and synaptic plasticity1,2. The levels of neurotrophins are important basis of learning and memory in The surprising discovery that neurotrophins and It is well established that the overall levels of neuro- vertebrates. their receptors do not exist in Drosophila melanogaster trophins determine the balance between cell survival or Caenorhabditis elegans reinforced the idea that these and APOPTOSIS during development. Neural activity has proteins are not absolutely necessary for the develop- profound effects on the levels of neurotrophins. Indeed, ment of neuronal circuits per se, but are involved in the idea that neurotrophins are crucial for synaptic plas- ‘higher-order’ activities. For example, neurotrophins ticity came from observations that they are synthesized and their receptors influence many aspects of neuronal and released in an activity-dependent manner7–9. NGF activity that result in the generation of new synaptic and brain-derived neurotrophic factor (BDNF) mes- 3 Skirball Institute of connections, which can be long lasting . Alterations in senger RNAs (mRNAs) are highly regulated by electrical Biomolecular Medicine, neurotrophin levels have profound effects on a wide vari- stimulation and epileptic activity10, and BDNF in par- New York University School ety of phenomena, including myelination, regeneration, ticular is rapidly released by neuronal activity during of Medicine, New York, pain, aggression, depression and substance abuse. periods of activity-dependent synaptic remodelling11–14. New York 10016, USA. The actions of neurotrophins depend on two differ- Studies of mice that express reduced levels of e-mail: 4 [email protected] ent transmembrane-receptor signalling systems — the neurotrophins have shown surprising effects on adult doi:10.1038/nrn1078 Trk receptor tyrosine kinases and the p75 neurotrophin brain function and behaviour. Mice that completely NATURE REVIEWS | NEUROSCIENCE VOLUME 4 | APRIL 2003 | 299 © 2003 Nature PublishingGroup REVIEWS Box 1 | Haploinsufficiency of neurotrophins NGFNT4, NT3 NGF, BDNF, BDNF NT3, NT4 NGF +/– mice • Decreased cholinergic innervation of the hippocampus15 • Deficiency in memory acquisition and retention15 • Loss of neurons of the peripheral nervous system121 BDNF +/– mice • Hyperphagia, obesity16–18 Death domain • Impairment of long-term potentiation19,20,122 • Elevated striatal dopamine levels123 TrkA TrkBTrkC p75 • Loss of mechanosensitivity124 Trk +=p75 High-affinity sites • Loss of neurons of the peripheral nervous system125,126 NT3 +/– mice • Deficient amygdala KINDLING activity127 • Cardiovascular defects128 • Reduced mechanoreceptors129 • Loss of neurons of the peripheral nervous system130 p75 Trk lack neurotrophins die during the first few weeks MAPK, NF-κB following birth. Heterozygous mice in which neuro- PI3K, JNK PLC-γ trophin levels are reduced by half are viable but, strik- ingly, they show other unanticipated deficits (BOX 1).For Figure 1 | Models of Trk and p75 receptor activation. example, lowering the level of NGF leads to several Neurotrophin binding results in dimerization of each receptor. APOPTOSIS Neurotrophins bind selectively to specific Trk receptors, 15 The process of programmed cell deficits in memory acquisition and retention . In the whereas all neurotrophins bind to p75. Trk receptors contain death, characterized by absence of normal levels of BDNF,mice show enhanced extracellular immunoglobulin G (IgG) domains for ligand distinctive morphological aggressiveness, hyperactivity and hyperphagia16–18. binding and a catalytic tyrosine kinase sequence in the changes in the nucleus and Intracerebroventricular infusion of BDNF or neuro- intracellular domain. Each receptor activates several signal cytoplasm, chromatin cleavage 17 transduction pathways5,34,35. The extracellular portion of p75 at regularly spaced sites, and the trophin 4 (NT4) reverses the hyperphagic phenotype . contains four cysteine-rich repeats, and the intracellular part endonucleolytic cleavage of In BDNF+/– heterozygous mice, 5-HT (5-hydroxy- contains a death domain. Neurotrophin binding to the p75 genomic DNA. tryptamine, serotonin)-mediated neuronal function is receptor mediates survival, cell migration and myelination135 abnormal in the forebrain, cortex, hippocampus and 36 LIGHT/DARK EXPLORATION through several signalling pathways . Interactions between TEST hypothalamus, and administration of the selective Trk and p75 receptors can lead to changes in the binding 27 This test depends on the natural 5-HT-reuptake inhibitor fluoxetine reduces the aggres- affinity for neurotrophins . BDNF, brain-derived neurotrophic tendency of rodents to explore sive behaviour, hyperphagia and hyperlocomotor activ- factor; JNK, Jun N-terminal kinase; MAPK, mitogen-activated the environment in the absence ity16. A conditional deletion of BDNF in the brains of protein kinase; NGF, nerve growth factor; NT, neurotrophin; PI3K, phosphatidylinositol 3-kinase; PLC-γ, phospholipase Cγ. of a threat and to retreat to an postnatal mice also leads to hyperphagia and hyperac- enclosed area when fearful. The animals are placed in an tivity, as well as to higher levels of anxiety as measured apparatus that has a dark and an by a LIGHT/DARK EXPLORATION TEST18. Therefore, the feeding illuminated compartment. phenotype and the other behavioural abnormalities are conserved dibasic amino-acid cleavage site to release Reduced exploration of the mediated by the action of BDNF in the central nervous carboxy-terminal mature proteins. The mature proteins, bright compartment and a reduced number of transitions system (CNS), not in the periphery. Abnormal behav- which are about 12 kDa in size, form stable, non-covalent between compartments are iours, indicative of impulse-control disorders, are also dimers, and are normally expressed at very low levels commonly interpreted as elicited by partial deletion of BDNF. during development. The amino-terminal half (or pro- measures of anxiety. Lack of BDNF also causes deficits in memory tasks; domain) of the pro-neurotrophin is believed to be for example, BDNF +/– mice show impairments in spatial important for the proper folding and intracellular FURIN An endopeptidase with memory. This is consistent with defects in LTP that are sorting of neurotrophins. specificity for the consensus found in the hippocampus. Interestingly, BDNF –/– and sequence Arg-X-Lys/Arg-Arg. BDNF +/– mice show the same deficits in LTP19,20, indi- Receptors encode specificity and responsiveness. Different cating that not only the availability of BDNF,but also its neurotrophins show binding specificity for particular KINDLING An experimental model of levels, can profoundly alter plasticity. receptors — NGF binds preferentially to tyrosine recep- epilepsy in which an increased tor kinase A (TrkA); BDNF and NT4 to TrkB; and neu- susceptibility to seizures arises Neurotrophins and their receptors rotrophin 3 (NT3) to TrkC (FIG. 1). These interactions after daily focal stimulation of The neurotrophins are initially synthesized as precur- have generally been considered to be of high affinity. specific brain areas (for example, sors or pro-neurotrophins, which are cleaved to produce However, in reality, the binding of NGF