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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. 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. Access through your institution Buy or subscribe This is a preview of subscription content,

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ROLES OF EPHRIN RECEPTORS ACROSS DIVERSE CELLULAR NICHES Article Open access 06 November 2024 EVOLUTION OF CENTRAL NEURAL CIRCUITS: STATE OF THE ART AND PERSPECTIVES Article 26 October 2022

NEUREXINS: MOLECULAR CODES FOR SHAPING NEURONAL SYNAPSES Article 08 January 2021 REFERENCES * McAllister, A., Katz, L. & Lo, D. Neurotrophins and synaptic plasticity. _Annu. Rev.

Neurosci._ 22, 295–318 (1999). CAS  PubMed  Google Scholar  * Poo, M. -M. Neurotrophins as synaptic modulators. _Nature Rev. Neurosci._ 2, 24–31 (2001). CAS  Google Scholar  * Huang, E.

& Reichardt, L. Neurotrophins: roles in neuronal development and function. _Annu. Rev. Neurosci._ 24, 677–736 (2001). CAS  PubMed  PubMed Central  Google Scholar  * Chao, M. V. &

Hempstead, B. L. p75 and trk: a two-receptor system. _Trends Neurosci._ 18, 321–326 (1995). CAS  PubMed  Google Scholar  * Kaplan, D. R. & Miller, F. D. Neurotrophin signal transduction

in the nervous system. _Curr. Opin. Neurobiol._ 10, 381–391 (2000). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Gall, C. & Isackson, P. Limbic seizures increase neuronal

production of messenger RNA for nerve growth factor. _Science_ 245, 758–761 (1989). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar 

* Wang, X. H. & Poo, M. -M. Potentiation of developing synapses by postsynaptic release of NT-4. _Neuron_ 19, 825–835 (1997). CAS  PubMed  Google Scholar  * Gall, C. Regulation of brain

neurotrophin expression by physiological activity. _Trends Pharmacol. Sci._ 13, 401–403 (1992). CAS  PubMed  Google Scholar  * 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). CAS  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Kohara, K., Kitamura, A.,

Morishima, M. & Tsumoto, T. Activity-dependent transfer of brain-derived neurotrophic factor to postsynaptic neurons. _Science_ 291, 2419–2423 (2001). CAS  PubMed  Google Scholar  *

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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  *

Kernie, S., Liebl, D. & Parada, L. BDNF regulates eating behavior and locomotor activity in mice. _EMBO J._ 19, 1290–1300 (2000). CAS  PubMed  PubMed Central  Google Scholar  * 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. CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Patterson, S. et al. Recombinant BDNF rescues

deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. _Neuron_ 16, 1137–1145 (1996). CAS  PubMed  Google Scholar  * Heymach, J. V. & Shooter, E. M. The

biosynthesis of neurotrophin heterodimers by transfected mammalian cells. _J. Biol. Chem._ 270, 12297–12304 (1995). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Dechant, G. et al. Expression

and binding characteristics of the BDNF receptor chick trkB. _Development_ 119, 545–558 (1993). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Arevalo, J. et al. TrkA immunoglobulin-like ligand binding domains inhibit spontaneous activation of

the receptor. _Mol. Cell Biol._ 20, 5908–5916 (2000). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed 

Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Bibel, M., Hoppe, E. & Barde, Y. Biochemical and functional interactions between the

neurotrophin receptors trk and p75NTR. _EMBO J._ 18, 616–622 (1999). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Ginty, D. & Segal, R. Retrograde neurotrophin

signaling: Trk-ing along the axon. _Curr. Opin. Neurobiol._ 12, 268–274 (2002). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Patapoutian, A. &

Reichardt, L. Trk receptors: mediators of neurotrophin action. _Curr. Opin. Neurobiol._ 11, 272–280 (2001). CAS  PubMed  Google Scholar  * Hempstead, B. The many faces of p75NTR. _Curr.

Opin. Neurobiol._ 12, 260–267 (2002). CAS  PubMed  Google Scholar  * Roux, P. & Barker, P. Neurotrophin signaling through the p75 neurotrophin receptor. _Prog. Neurobiol._ 67, 203–233

(2002). CAS  PubMed  Google Scholar  * Lonze, B. & Ginty, D. Function and regulation of CREB family transcription factors in the nervous system. _Neuron_ 35, 605–623 (2002). CAS  PubMed

  Google Scholar  * York, R. et al. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. _Nature_ 392, 622–626 (1998). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google

Scholar  * Dowling, P. et al. Upregulated p75NTR neurotrophin receptor on glial cells in MS plaques. _Neurology_ 53, 1676–1682 (1999). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google

Scholar  * Beattie, M. et al. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. _Neuron_ 36, 375–386 (2002). CAS  PubMed  PubMed Central  Google Scholar  *

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). CAS  PubMed

  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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. CAS  PubMed  Google Scholar  * Chao, M. V. Growth factor signaling: where is the

specificity? _Cell_ 68, 995–997 (1992). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Kang, H. & Schuman, E. M. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult

hippocampus. _Science_ 267, 1658–1662 (1995). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google

Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Schuman, E. Neurotrophin regulation of synaptic transmission. _Curr.

Opin. Neurobiol._ 9, 105–109 (1999). CAS  PubMed  Google Scholar  * Schinder, A. & Poo, M. -M. The neurotrophin hypothesis for synaptic plasticity. _Trends Neurosci._ 23, 639–645 (2000).

CAS  PubMed  Google Scholar  * 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). CAS 

PubMed  Google Scholar  * Minichiello, L. et al. Essential role for TrkB receptors in hippocampus-mediated learning. _Neuron_ 24, 401–414 (1999). CAS  PubMed  Google Scholar  * Minichiello,

L. et al. Mechanism of TrkB-mediated hippocampal long-term potentiation. _Neuron_ 36, 121–137 (2002). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  *

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). CAS  PubMed 

Google Scholar  * Dalva, M. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. _Cell_ 103, 945–956 (2000). CAS  PubMed  Google Scholar  * Grunwald,

I. et al. Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. _Neuron_ 32, 1027–1040 (2001). CAS  PubMed  Google Scholar  * Henderson, J. et al. The

receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. _Neuron_ 32, 1041–1056 (2001). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Montell, C., Birnbaumer, L.

& Flockerzi, V. The TRP channels, a remarkably functional family. _Cell_ 108, 595–598 (2002). CAS  PubMed  Google Scholar  * 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. CAS  PubMed  Google Scholar  * Caterina, M. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. _Nature_ 389, 816–824 (1997). CAS  PubMed  Google

Scholar  * Shu, X. & Mendell, L. Neurotrophins and hyperalgesia. _Proc. Natl Acad. Sci. USA_ 96, 7693–7696 (1999). CAS  PubMed  PubMed Central  Google Scholar  * 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. CAS  PubMed  Google Scholar  * Johagen, M. et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease.

_Dement. Geriat. Cogn._ 9, 246–257 (1998). Google Scholar  * Thoenen, H. & Sendtner, M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic

approaches. _Nature Neurosci._ 5, S1046–S1050 (2002). Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  Google Scholar  * 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). CAS  PubMed 

Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  *

Kovalchuk, Y., Hanse, E., Kafitz, K. & Konnerth, A. Postsynaptic induction of BDNF-mediated long-term potentiation. _Science_ 295, 1729–1734 (2002). CAS  PubMed  Google Scholar  *

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).

CAS  PubMed  PubMed Central  Google Scholar  * Carroll, R., Beattie, E., von Zastrow, M. & Malenka, R. Role of AMPA receptor endocytosis in synaptic plasticity. _Nature Rev. Neurosci._

2, 315–324 (2001). CAS  Google Scholar  * Blum, R., Kafitz, K. & Konnerth, A. Neurotrophin-evoked depolarization requires the sodium channel NaV1.9. _Nature_ 419, 687–693 (2002). CAS 

PubMed  Google Scholar  * 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. CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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).

CAS  PubMed  Google Scholar  * Arevalo, J. et al. A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation. _Oncogene_ 20, 1229–1234 (2001). CAS 

PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Luttrell, L., Daaka, Y. & Lefkowitz, R. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. _Curr. Opin. Cell Biol._ 11,

177–183 (1999). CAS  PubMed  Google Scholar  * Lee, F. & Chao, M. Activation of Trk neurotrophin receptors in the absence of neurotrophins. _Proc. Natl Acad. Sci. USA_ 98, 3555–3560

(2001). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google

Scholar  * 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). CAS 

PubMed  PubMed Central  Google Scholar  * Kotecha, S. et al. A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. _Neuron_ 35,

1111–1122 (2002). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google

Scholar  * Ledent, C. et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. _Nature_ 388, 674–678 (1997). CAS  PubMed  Google Scholar  *

Airaksinen, M. & Saarma, M. The GDNF family: signalling, biological functions and therapeutic value. _Nature Rev. Neurosci._ 3, 383–394 (2002). CAS  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Duman, R., Heninger, G. & Nestler, E. A molecular and cellular theory of depression. _Arch. Gen. Psychiatry_ 54, 597–606 (1997). CAS 

PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Fournier, A., GrandPre, T. &

Strittmatter, S. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. _Nature_ 409, 341–346 (2001). CAS  PubMed  Google Scholar  * Wang, K. et al.

Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. _Nature_ 417, 941–944 (2002). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Domeniconi, M. et

al. Myelin-associated glycoprotein interacts with the Nogo-66 receptor to inhibit neurite outgrowth. _Neuron_ 35, 283–290 (2002). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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. CAS  PubMed  Google Scholar  * 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. CAS  PubMed  PubMed Central 

Google Scholar  * Yamashita, T., Tucker, K. & Barde, Y. Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. _Neuron_ 24, 585–593 (1999). CAS  PubMed 

Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Dobrowsky, R. T. & Carter, B. D. p75 neurotrophin receptor signaling: mechanisms for

neurotrophic modulation of cell stress? _J. Neurosci. Res._ 61, 237–243 (2000). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS

  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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. CAS  PubMed  Google Scholar  * Ventriglia, M. et al. Association between the BDNF 196 A/G polymorphism and

sporadic Alzheimer's disease. _Mol. Psychiatry_ 7, 136–137 (2002). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Ueyama, T. et al.

Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain. _Neurosci. Res._ 28, 103–110 (1997). CAS  PubMed  Google Scholar  * 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. CAS  PubMed

  PubMed Central  Google Scholar  * Elliott, T. & Shadbolt, N. Competition for neurotrophic factors: mathematical analysis. _Neural Comput._ 10, 1939–1981 (1998). CAS  PubMed  Google

Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Dluzen, D. et al. Evaluation of nigrostriatal

dopaminergic function in adult +/+ and +/− BDNF mutant mice. _Exp. Neurol._ 170, 121–128 (2001). CAS  PubMed  Google Scholar  * Carroll, P., Lewin, G., Koltzenburg, M., Toyka, K. &

Thoenen, H. A role for BDNF in mechanosensation. _Nature Neurosci._ 1, 42–46 (1998). CAS  PubMed  Google Scholar  * Ernfors, P., Lee, K. F. & Jaenisch, R. Mice lacking brain-derived

neurotrophic factor develop with sensory deficits. _Nature_ 368, 147–150 (1994). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google

Scholar  * Airaksinen, M. et al. Specific subtypes of cutaneous mechanoreceptors require neurotrophin-3 following peripheral target innervation. _Neuron_ 16, 287–295 (1996). CAS  PubMed 

Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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. Google Scholar  * Brown, M., Ye, J., Rawson, R. &

Goldstein, J. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. _Cell_ 100, 391–398 (2000). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Cosgaya, J. M., Chan, J. R. & Shooter, E. M. The neurotrophin receptor p75NTR as a positive modulator of myelination.

_Science_ 298, 1245–1248 (2002). CAS  PubMed  Google Scholar  * Wu, C., Lai, C. F. & Mobley, W. C. Nerve growth factor activates persistent Rap1 signaling in endosomes. _J. Neurosci._

21, 5406–5416 (2001). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Koliatsos, V.,

Crawford, T. & Price, D. Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons. _Brain Res._ 549, 297–304 (1991). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Friedman, W. Neurotrophins induce death of hippocampal

neurons via the p75 receptor. _J. Neurosci._ 20, 6340–6346 (2000). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * Lemke, G. & Chao, M. V. Axons regulate Schwann cell expression of

major myelin and NGF receptor genes. _Development_ 102, 499–504 (1988). CAS  PubMed  Google Scholar  * 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). CAS 

PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  PubMed Central  Google Scholar  * 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). CAS  PubMed  Google Scholar  * Hu, X. -Y. et al. Increased p75NTR expression in

hippocampal neurons containing hyperphosphorylated τ in Alzheimer patients. _Exp. Neurol._ 178, 104–111 (2002). CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The

assistance of Albert Kim is gratefully acknowledged. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New

York, 10016, New York, USA Moses V. Chao Authors * Moses V. Chao View author publications You can also search for this author inPubMed Google Scholar RELATED LINKS RELATED LINKS DATABASES

SWISS-PROT BDNF CREB GDNF JNK Kv1.3 MAG Nav1.9 NF-κB NGF Nogo PACAP Semaphorin 3A Shc TrkA TrkB TrkC Tumour necrosis factor OMIM Alzheimer disease 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

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 Download citation * Issue

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