Key Points
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
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.
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References
McAllister, A., Katz, L. & Lo, D. Neurotrophins and synaptic plasticity. Annu. Rev. Neurosci. 22, 295–318 (1999).
Poo, M. -M. Neurotrophins as synaptic modulators. Nature Rev. Neurosci. 2, 24–31 (2001).
Huang, E. & Reichardt, L. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).
Chao, M. V. & Hempstead, B. L. p75 and trk: a two-receptor system. Trends Neurosci. 18, 321–326 (1995).
Kaplan, D. R. & Miller, F. D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391 (2000).
Dechant, G. & Barde, Y. -A. The neurotrophin receptor p75NTR: novel functions and implications for diseases of the nervous system. Nature Neurosci. 5, 1131–1136 (2002).
Gall, C. & Isackson, P. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 245, 758–761 (1989).
Blochl, A. & Thoenen, H. Characterization of nerve growth factor release from hippocampal neurons: evidence for a constitutive and an unconventional sodium-dependent regulated pathway. Eur. J. Neurosci. 7, 1220–1228 (1995).
Wang, X. H. & Poo, M. -M. Potentiation of developing synapses by postsynaptic release of NT-4. Neuron 19, 825–835 (1997).
Gall, C. Regulation of brain neurotrophin expression by physiological activity. Trends Pharmacol. Sci. 13, 401–403 (1992).
Schoups, A., Elliott, R., Friedman, W. & Black, I. NGF and BDNF are differentially modulated by visual experience in the developing geniculocortical pathway. Brain Res. Dev. 86, 326–334 (1995).
Lein, E., Hohn, A. & Shatz, C. Dynamic regulation of BDNF and NT-3 expression during visual system development. J. Comp. Neurol. 420, 1–18 (2000).
Kohara, K., Kitamura, A., Morishima, M. & Tsumoto, T. Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons. Science 291, 2419–2423 (2001).
Balkowiec, A. & Katz, D. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J. Neurosci. 22, 10399–10407 (2002).
Chen, K. et al. Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory deficits. J. Neurosci. 17, 7288–7296 (1997).
Lyons, W. E. et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc. Natl Acad. Sci. USA 96, 15239–15244 (1999).
Kernie, S., Liebl, D. & Parada, L. BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 19, 1290–1300 (2000).
Rios, M. et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15, 1748–1757 (2001). Profound effects on feeding and aggressive behaviours have been observed in three different lines of mice with reduced levels of BDNF. These results indicate that a partial depletion of BDNF can have a key role in regulating behavioural responses, in this case, through serotonergic abnormalities.
Korte, M. et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl Acad. Sci. USA 92, 8856–8860 (1995).
Patterson, S. et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16, 1137–1145 (1996).
Heymach, J. V. & Shooter, E. M. The biosynthesis of neurotrophin heterodimers by transfected mammalian cells. J. Biol. Chem. 270, 12297–12304 (1995).
Mowla, S. J. et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J. Biol. Chem. 276, 12660–12666 (2001).
Dechant, G. et al. Expression and binding characteristics of the BDNF receptor chick trkB. Development 119, 545–558 (1993).
Mahadeo, D., Kaplan, L., Chao, M. V. & Hempstead, B. L. High affinity nerve growth factor binding displays a faster rate of association than p140(trk) binding — implications for multisubunit polypeptide receptors. J. Biol. Chem. 269, 6884–6891 (1994).
Schropel, A., von Schack, D., Dechant, G. & Barde, Y. -A. Early expression of the nerve growth factor receptor ctrkA in chick sympathetic and sensory ganglia. Mol. Cell. Neurosci. 6, 544–556 (1995).
Arevalo, J. et al. TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of the receptor. Mol. Cell Biol. 20, 5908–5916 (2000).
Esposito, D. et al. The cytoplasmic and transmembrane domains of the p75 and TrkA receptors regulate high affinity binding to nerve growth factor. J. Biol. Chem. 276, 32687–32695 (2001).
Hempstead, B. L., Martin-Zanca, D., Kaplan, D. R., Parada, L. F. & Chao, M. V. High-affinity NGF binding requires co-expression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350, 678–683 (1991).
Benedetti, M., Levi, A. & Chao, M. V. Differential expression of nerve growth factor receptors leads to altered binding affinity and neurotrophin responsiveness. Proc. Natl Acad. Sci. USA 90, 7859–7863 (1993).
Bibel, M., Hoppe, E. & Barde, Y. Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. EMBO J. 18, 616–622 (1999).
Baloh, R., Enomoto, H., Johnson, E. & Milbrandt, J. The GDNF family ligands and receptors — implications for neural development. Curr. Opin. Neurobiol. 10, 103–110 (2000).
Ginty, D. & Segal, R. Retrograde neurotrophin signaling: Trk-ing along the axon. Curr. Opin. Neurobiol. 12, 268–274 (2002).
Grimes, M., Beattie, E. & Mobley, W. A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA. Proc. Natl Acad. Sci. USA 94, 9909–9914 (1997).
Patapoutian, A. & Reichardt, L. Trk receptors: mediators of neurotrophin action. Curr. Opin. Neurobiol. 11, 272–280 (2001).
Hempstead, B. The many faces of p75NTR. Curr. Opin. Neurobiol. 12, 260–267 (2002).
Roux, P. & Barker, P. Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol. 67, 203–233 (2002).
Lonze, B. & Ginty, D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623 (2002).
York, R. et al. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392, 622–626 (1998).
Majdan, M. & Miller, F. Neuronal life and death decisions: functional antagonism between the Trk and p75 neurotrophin receptors. Int. J. Dev. Neurosci. 17, 153–161 (1999).
Dowling, P. et al. Upregulated p75NTR neurotrophin receptor on glial cells in MS plaques. Neurology 53, 1676–1682 (1999).
Roux, P., Colicos, M., Barker, P. & Kennedy, T. p75 neurotrophin receptor expression is induced in apoptotic neurons after seizure. J. Neurosci. 19, 6887–6896 (1999).
Beattie, M. et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron 36, 375–386 (2002).
Harrington, A. W., Kim, J. Y. & Yoon, S. O. Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis. J. Neurosci. 22, 156–166 (2002).
Khursigara, G. et al. A pro-survival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor interacting protein 2. J. Neurosci. 21, 5854–5863 (2001).
DeFreitas, M., McQuillen, P. & Shatz, C. A novel p75NTR signaling pathway promotes survival, not death, of immunopurified neocortical subplate neurons. J. Neurosci. 21, 5121–5129 (2001).
Lee, R., Kermani, P., Teng, K. & Hempstead, B. Regulation of cell survival by secreted proneurotrophins. Science 294, 1945–1948 (2001). The precursor forms of neurotrophins have been implicated in the folding and processing of the mature proteins. This paper indicates that the pro-sequence of NGF preferentially binds to the p75 receptor.
Chao, M. V. Growth factor signaling: where is the specificity? Cell 68, 995–997 (1992).
Lohof, A. M., Ip, N. & Poo, M. -M. Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature 363, 350–353 (1993).
Kang, H. & Schuman, E. M. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267, 1658–1662 (1995).
Levine, E. S., Dreyfus, C. F., Black, I. B. & Plummer, M. R. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc. Natl Acad. Sci. USA 92, 8074–8077 (1995).
Xie, C. et al. Deficient long-term memory and long-lasting long-term potentiation in mice with a targeted deletion of neurotrophin-4. Proc. Natl Acad. Sci. USA 97, 8116–8121 (2000).
Korte, M. et al. Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. Proc. Natl Acad. Sci. USA 93, 12547–12552 (1996).
Schuman, E. Neurotrophin regulation of synaptic transmission. Curr. Opin. Neurobiol. 9, 105–109 (1999).
Schinder, A. & Poo, M. -M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 23, 639–645 (2000).
Yang, F. et al. PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation. Nature Neurosci. 4, 19–28 (2001).
Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401–414 (1999).
Minichiello, L. et al. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36, 121–137 (2002).
Peterson, D. A., Dickinson-Anson, H. A., Leppert, J. T., Lee, K. -F. & Gage, F. H. Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. J. Comp. Neurol. 404, 1–20 (1999).
von Schack, D. et al. Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nature Neurosci. 4, 977–978 (2001).
Dalva, M. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945–956 (2000).
Grunwald, I. et al. Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32, 1027–1040 (2001).
Henderson, J. et al. The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32, 1041–1056 (2001).
Takasu, M., Dalva, M., Zigmond, R. & Greenberg, M. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 491–495 (2002).
Montell, C., Birnbaumer, L. & Flockerzi, V. The TRP channels, a remarkably functional family. Cell 108, 595–598 (2002).
Li, H., Xu, X. & Montell, C. Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron 24, 261–273 (1999). BDNF binding to TrkB produced a rapid influx of cations through TRPC3 that was dependent on activation of phospholipase C. An interaction between TrkB receptors and TRPC3 ion channels was observed, indicating that ion channels might be closely associated with receptor tyrosine kinases.
Caterina, M. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).
Shu, X. & Mendell, L. Neurotrophins and hyperalgesia. Proc. Natl Acad. Sci. USA 96, 7693–7696 (1999).
Chuang, H. -h. et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957–962 (2001). This study shows that the capsaicin (TRPV1) receptor is activated through NGF binding to TrkA receptors. The interaction between a receptor tyrosine kinase and a pain-related channel provides a mechanism for the ability of sensory neurons to respond to NGF-mediated heat sensitivity and also points to a mechanism for the heightened hyperalgesia that is observed after administration of neurotrophins in clinical trials of neurodegenerative diseases.
Johagen, M. et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement. Geriat. Cogn. 9, 246–257 (1998).
Thoenen, H. & Sendtner, M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nature Neurosci. 5, S1046–S1050 (2002).
Lin, S. et al. BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities. Brain Res. Mol. Brain Res. 55, 20–27 (1998).
Tucker, K. & Fadool, D. Neurotrophin modulation of voltage-gated potassium channels in rat through TrkB receptors is time and sensory experience dependent. J. Physiol. (Lond.) 542, 413–429 (2002).
Figurov, A., Pozzo-Miller, L., Olafsson, T., Wang, B. & Lu, B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709 (1996).
Gottschalk, W., Pozzo-Miller, L., Figurov, A. & Lu, B. Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J. Neurosci. 18, 6830–6839 (1998).
Xu, B. et al. The role of brain-derived neurotrophic factors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J. Neurosci. 20, 6888–6897 (2000).
Kovalchuk, Y., Hanse, E., Kafitz, K. & Konnerth, A. Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295, 1729–1734 (2002).
Balkowiec, A., Kunze, D. & Katz, D. Brain-derived neurotrophic factor acutely inhibits AMPA-mediated currents in developing sensory relay neurons. J. Neurosci. 20, 1904–1911 (2000).
Carroll, R., Beattie, E., von Zastrow, M. & Malenka, R. Role of AMPA receptor endocytosis in synaptic plasticity. Nature Rev. Neurosci. 2, 315–324 (2001).
Blum, R., Kafitz, K. & Konnerth, A. Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. Nature 419, 687–693 (2002).
Kafitz, K., Rose, C., Thoenen, H. & Konnerth, A. Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 401, 918–921 (1999). A remarkably rapid response of a sodium channel by BDNF treatment is documented in references 79 and 80.
Choi, D. -Y., Toledo-Aral, J., Segal, R. & Halegoua, S. Sustained signaling by phospholipase C-γ mediates nerve growth factor-triggered gene expression. Mol. Cell Biol. 21, 2695–2705 (2001).
Toledo-Aral, J., Brehm, P., Halegoua, S. & Mandel, G. A single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction. Neuron 14, 607–611 (1995).
Arevalo, J. et al. A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation. Oncogene 20, 1229–1234 (2001).
Daub, H., Weiss, F. U., Wallasch, C. & Ullrich, A. Role of transactivation of the EGF receptor in signalling by G-protein coupled receptors. Nature 379, 557–560 (1996).
Luttrell, L., Daaka, Y. & Lefkowitz, R. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr. Opin. Cell Biol. 11, 177–183 (1999).
Lee, F. & Chao, M. Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc. Natl Acad. Sci. USA 98, 3555–3560 (2001).
Lee, F. S., Ragagopal, R., Kim, A. H., Chang, P. & Chao, M. V. Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides. J. Biol. Chem. 277, 9096–9102 (2002).
Takei, N. et al. Pituitary adenylate cyclase-activating polypeptide promotes the survival of basal forebrain cholinergic neurons in vitro and in vivo: comparison with effects of nerve growth factor. Eur. J. Neurosci. 12, 2273–2280 (2000).
Williams, L. R. et al. Continuous infusion of NGF prevents basal forebrain neuronal death after fimbria fornix transection. Proc. Natl Acad. Sci. USA 83, 9231–9235 (1986).
Kotecha, S. et al. A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron 35, 1111–1122 (2002).
Otto, C. et al. Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice. J. Neurosci. 21, 5520–5527 (2001).
Hashimoto, H., Shintani, N. & Baba, A. Higher brain functions of PACAP and a homologous Drosophila memory gene amnesiac: insights from knockouts and mutants. Biochem. Biophys. Res. Commun. 297, 427–432 (2002).
Ledent, C. et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388, 674–678 (1997).
Airaksinen, M. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. Nature Rev. Neurosci. 3, 383–394 (2002).
Tsui-Pierchala, B., Milbrandt, J. & Johnson, E. NGF utilizes c-Ret via a novel GFL-independent, inter-RTK signaling mechanism to maintain the trophic status of mature sympathetic neurons. Neuron 33, 261–273 (2002).
Duman, R., Heninger, G. & Nestler, E. A molecular and cellular theory of depression. Arch. Gen. Psychiatry 54, 597–606 (1997).
Cai, D., Shen, Y., DeBellard, M., Tang, S. & Filbin, M. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101 (1999).
Luo, Y., Raible, D. & Raper, J. Collapsin, a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75, 217–227 (1993).
Tuttle, R. & O'Leary, D. Neurotrophins rapidly modulate growth cone response in the axon guidance molecule, collapsin-1. Mol. Cell. Neurosci. 11, 1–8 (1998).
Dontchev, V. & Letourneau, P. Nerve growth factor and semaphorin 3A signaling pathways interact in regulating sensory neuronal growth cone motility. J. Neurosci. 22, 6659–6669 (2002).
Fournier, A., GrandPre, T. & Strittmatter, S. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001).
Wang, K. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002).
Liu, B., Fournier, A., GrandPre, T. & Strittmatter, S. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297, 1190–1193 (2002).
Domeniconi, M. et al. Myelin-associated glycoprotein interacts with the Nogo-66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290 (2002).
Wang, K., Kim, J., Sivasankaran, R., Segal, R. & He, Z. p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78 (2002).
Wong, S. et al. A p75NTR and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nature Neurosci. 5, 1302–1308 (2002). These papers merge neurotrophin receptor signalling to inhibition of regeneration in the CNS through the actions of three unrelated proteins — Nogo, p75 and MAG.
Yamashita, T., Higuchi, H. & Tohyama, M. The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J. Cell Biol. 157, 565–570 (2002). An important link is made between the ability of MAG to block axonal growth and Rho activity through the p75 receptor. The results led to the experiments showing that the p75 and Nogo receptors act in a complex.
Yamashita, T., Tucker, K. & Barde, Y. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24, 585–593 (1999).
Walsh, G., Krol, K., Crutcher, K. & Kawaja, M. Enhanced neurotrophin-induced axon growth in myelinated portions of the CNS in mice lacking the p75 neurotrophin receptor. J. Neurosci. 19, 4155–4168 (1999).
Dobrowsky, R. T. & Carter, B. D. p75 neurotrophin receptor signaling: mechanisms for neurotrophic modulation of cell stress? J. Neurosci. Res. 61, 237–243 (2000).
Cosgaya, J. & Shooter, E. Binding of nerve growth factor to its p75 receptor in stressed cells induces selective IκB-β degradation and NF-κB nuclear translocation. J. Neurochem. 79, 391–399 (2001).
Sklar, P. et al. Family-based asssociation study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Mol. Psychiatry 7, 579–593 (2002).
Neves-Pereira, M. et al. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am. J. Hum. Genet. 71, 651–655 (2002).
Sen, S. et al. A BDNF coding variant is associated with the NEO personality inventory domain neuroticism, a risk factor for depression. Neuropsychopharmacology 28, 397–401 (2003).
Egan, M. et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257–269 (2003). This study is the first to show that a human polymorphism in BDNF is associated with memory deficits. A single amino acid variation in the pro-domain of BDNF accounts for the ability of BDNF to undergo proper secretion.
Ventriglia, M. et al. Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Mol. Psychiatry 7, 136–137 (2002).
Smith, M., Makino, S., Kvetnansky, R. & Post, R. Stress alters the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15, 1768–1777 (1995).
Ueyama, T. et al. Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain. Neurosci. Res. 28, 103–110 (1997).
Shirayama, Y., Chen, A., Nakagawa, S., Russell, D. & Duman, R. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251–3261 (2002). Administration of exogenous BDNF exerted profound positive effects in forced swim and learned helplessness assays, indicating that BDNF signalling might be related to depression.
Elliott, T. & Shadbolt, N. Competition for neurotrophic factors: mathematical analysis. Neural Comput. 10, 1939–1981 (1998).
Crowley, C. et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76, 1001–1012 (1994).
Bartoletti, A. et al. Heterozygous knock-out mice for brain-derived neurotrophic factor show a pathway-specific impairment of long-term potentiation but normal critical period for monocular deprivation. J. Neurosci. 22, 10072–10077 (2002).
Dluzen, D. et al. Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/− BDNF mutant mice. Exp. Neurol. 170, 121–128 (2001).
Carroll, P., Lewin, G., Koltzenburg, M., Toyka, K. & Thoenen, H. A role for BDNF in mechanosensation. Nature Neurosci. 1, 42–46 (1998).
Ernfors, P., Lee, K. F. & Jaenisch, R. Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368, 147–150 (1994).
Bianchi, L. et al. Degeneration of vestibular neurons in late embryogenesis of both heterozygous and homozygous BDNF null mutant mice. Development 122, 1965–1973 (1996).
Elmer, E. et al. Suppressed kindling epileptogenesis and perturbed BDNF and TrkB gene regulation in NT-3 mutant mice. Exp. Neurol. 145, 93–103 (1997).
Donovan, M., Hahn, R., Tessarollo, L. & Hempstead, B. Neurotrophin-3 is required for mammalian cardiac development: identification of an essential nonneuronal neurotrophin function. Nature Genet. 14, 210–213 (1996).
Airaksinen, M. et al. Specific subtypes of cutaneous mechanoreceptors require neurotrophin-3 following peripheral target innervation. Neuron 16, 287–295 (1996).
Ernfors, P., Lee, K. -F., Kucera, J. & Jaenisch, R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell 77, 503–512 (1994).
DiStefano, P., Chelsea, D., Schick, C. & McKelvy, J. Involvement of a metalloprotease in low-affinity nerve growth factor receptor truncation: inhibition of truncation in vitro and in vivo. J. Neurosci. 13, 2405–2414 (1993).
Schecterson, L., Kanning, K., Hudson, M. & Bothwell, M. The neurotrophin receptor p75 is cleaved by regulated intramembranous proteolysis. Soc. Neurosci. Abstr. 27, 822.10 (2002). Intramembranous cleavage of Notch, the amyloid precursor protein and ErbB4 receptors generates intracellular cytoplasmic fragments that produce marked changes in signalling and transcriptional activities. The cleavage of p75 by a γ-secretase reveals a new mechanism for transmitting neurotrophin signals from the cell surface to intracellular locations.
Brown, M., Ye, J., Rawson, R. & Goldstein, J. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391–398 (2000).
Fahnestock, M., Michalski, B., Xu, B. & Coughlin, M. The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease. Mol. Cell. Neurosci. 18, 210–220 (2001).
Cosgaya, J. M., Chan, J. R. & Shooter, E. M. The neurotrophin receptor p75NTR as a positive modulator of myelination. Science 298, 1245–1248 (2002).
Wu, C., Lai, C. F. & Mobley, W. C. Nerve growth factor activates persistent Rap1 signaling in endosomes. J. Neurosci. 21, 5406–5416 (2001).
Lee, F., Rajagopal, R., Kim, A., Chang, P. & Chao, M. Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides. J. Biol. Chem. 277, 9096–9102 (2002).
Chen, M. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monclonal antibody IN-1. Nature 403, 434–439 (2000).
Ernfors, P., Henschen, A., Olson, L. & Persson, H. Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron 2, 1605–1613 (1989).
Koliatsos, V., Crawford, T. & Price, D. Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons. Brain Res. 549, 297–304 (1991).
Hayes, R., Wiley, R. & Armstrong, D. Induction of nerve growth factor receptor (p75NGFr) mRNA within hypoglossal motoneurons following axonal injury. Brain Res. Mol. Brain Res. 15, 291–297 (1992).
Martinez-Murillo, R., Fernandez, A., Bentura, M. & Rodrigo, J. Subcellular localization of low-affinity nerve growth factor receptor-immunoreactive protein in adult rat Purkinje cells following traumatic injury. Exp. Brain Res. 119, 47–57 (1998).
Friedman, W. Neurotrophins induce death of hippocampal neurons via the p75 receptor. J. Neurosci. 20, 6340–6346 (2000).
Kokaia, Z., Andsberg, G., Martinez-Serrano, A. & Lindvall, O. Focal cerebral ischemia in rats induces expression of p75 neurotrophin receptor in resistant striatal cholinergic neurons. Neuroscience 84, 1113–1125 (1998).
Park, J., Lee, J., Sato, T. & Koh, J. Co-induction of p75NTR and p75NTR-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat. J. Neurosci. 20, 9096–9103 (2000).
Mufson, E. & Kordower, J. Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer's disease. Proc. Natl Acad. Sci. USA 89, 569–573 (1992).
Lemke, G. & Chao, M. V. Axons regulate Schwann cell expression of major myelin and NGF receptor genes. Development 102, 499–504 (1988).
Taniuchi, M., Clark, H., Schweitzer, J. & Johnson, E. Expression of nerve growth factor receptors by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by axonal contact, and binding properties. J. Neurosci. 8, 664–681 (1988).
Chang, A., Nishiyama, A., Peterson, J., Prineas, J. & Trapp, B. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 20, 6404–6412 (2000).
Calza, L., Giardino, L., Pozza, M., Micera, A. & Aloe, L. Time-course changes of nerve growth factor, corticotropin-releasing hormone, and nitric oxide synthase isoforms and their possible role in the development of inflammatory response in experimental allergic encephalomyelitis. Proc. Natl Acad. Sci. USA 94, 3368–3373 (1997).
Nataf, S. et al. Low affinity NGF receptor expression in the central nervous system during experimental allergic encephalomyelitis. J. Neurosci. Res. 52, 83–92 (1998).
Hu, X. -Y. et al. Increased p75NTR expression in hippocampal neurons containing hyperphosphorylated τ in Alzheimer patients. Exp. Neurol. 178, 104–111 (2002).
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The assistance of Albert Kim is gratefully acknowledged.
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Glossary
- LONG-TERM POTENTIATION
-
(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.
- APOPTOSIS
-
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.
- LIGHT/DARK EXPLORATION TEST
-
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.
- FURIN
-
An endopeptidase with specificity for the consensus sequence Arg-X-Lys/Arg-Arg.
- KINDLING
-
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.
- CONDITIONAL MUTATION
-
A mutation that can be selectively targeted to specific organs (or cell types within an organ) or induced at a specific developmental stage.
- POLYMORPHISM
-
The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.
- LEARNED HELPLESSNESS
-
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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Chao, M. Neurotrophins and their receptors: A convergence point for many signalling pathways. Nat Rev Neurosci 4, 299–309 (2003). https://doi.org/10.1038/nrn1078
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DOI: https://doi.org/10.1038/nrn1078
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