trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor

Squinto, Stephen P.; Stitt, Trevor N.; Aldrich, Thomas H.; Davis, Samuel; Blanco, Stella M.; Radziejewski, Czeslaw; Glass, David J.; Masiakowski, Piotr; Furth, Mark E.; Valenzuela, David M.; DiStefano, Peter S.; Yancopouloš, George D.

doi:10.1016/0092-8674(91)90395-f

Cited by 784 publications

(278 citation statements)

References 39 publications

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“…Moreover, NT-3, in this study, was considerably less potent than BDNF in promoting the survival of serotonergic axons after PCA, which remarkably parallels the relative potencies of these neurotrophins in augmenting 5-HT metabolism and analgesia (Siuciak et al, 1994). NGF and BDNF activate high affinity TrkA and TrkB receptors, respectively, while NT-3 preferentially activates TrkC and less potently stimulates the TrkB receptor (Kaplan et al, 1991;Lamballe et al, 1991;Squint0 et al, 1991). Thus, our findings suggest that the TrkB receptor mediates the neurotrophic effects of BDNF on serotonergic neurons.…”

Section: Discussionmentioning

confidence: 96%

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

et al. 1995

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A pathology of brain serotonergic (5-HT) systems has been found in psychiatric disturbances, normal aging and in neurodegenerative disorders including Alzheimer's and Parkinson's disease. Despite the clinical importance of 5-HT, little is known about the endogenous factors that have neurotrophic influences upon 5-HT neurons. The present study examined whether chronic pain parenchymal administration of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or NGF could prevent the severe degenerative loss of serotonergic axons normally caused by the selective 5-HT neurotoxin p-chloroamphetamine (PCA). The neurotrophins (5–12 micrograms/d) or the control substances (cytochrome c or PBS vehicle) were continuously infused into the rat frontoparietal cortex using an osmotic minipump. One week later, rats were subcutaneously administered PCA (10 mg/kg) or vehicle, and the 5-HT innervation was evaluated after two more weeks of neurotrophin infusion. As revealed with 5-HT immunocytochemistry, BDNF infusions into the neocortex of intact (non-PCA-lesioned) rats caused a substantial increase in 5-HT axon density in a 3 mm diameter region surrounding the cannula tip. In PCA-lesioned rats, intracortical infusions of BDNF completely prevented the severe neurotoxin-induced loss of 5-HT axons near the infusion cannula. In contrast, cortical infusions of vehicle or the control protein cytochrome c did not alter the density of serotonergic axons in intact animals, nor did control infusions prevent the loss of 5-HT axons in PCA-treated rats. NT-3 caused only a modest sparing of the 5-HT innervation in PCA-treated rats, and NGF failed to prevent the loss of 5-HT axon density. The immunocytochemical data were supported by neurochemical evaluations which showed that BDNF attenuated the PCA-induced loss of 5-HT and 5- HIAA contents and 3H-5-HT uptake near the infusion cannula. Thus, BDNF can promote the sprouting of mature, uninjured serotonergic axons and dramatically enhance the survival or sprouting of 5-HT axons normally damaged by the serotonergic neurotoxin PCA.

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Section: Discussionmentioning

confidence: 96%

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

et al. 1995

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“…Kim et al (1994) reported previously that neurotrophin-3 (NT-3), another member of neurotrophins, inhibits GABA A synaptic transmission in cultured embryonic cortical neurons. NT-3 primarily binds to TrkC but also can activate TrkB (Soppet et al, 1991;Squinto et al, 1991). Therefore, it was not clear whether TrkB participates in the regulation of GABA A receptor function.…”

Section: Inhibition Of Gaba a Receptor-mediated Ipscs By Bdnfmentioning

confidence: 99%

“…BDNF specifically binds to TrkB, a neurotrophin receptor, including the catalytic domain of tyrosine kinase (Soppet et al, 1991;Squinto et al, 1991). BDNF failed to reduce the amplitude of IPSCs when the recorded neuron was loaded intracellularly with K252a as well as when hippocampal slices were pretreated with K252a.…”

Section: Involvement Of Postsynaptic Trkb Activationmentioning

confidence: 99%

Inhibition of GABA_ASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus

1997

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Brain-derived neurotrophic factor (BDNF) is one of neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. Although the expression of BDNF and its receptor TrkB still occurs in the adult stage, their physiological role in the mature CNS is not fully understood. In the present study we examined in detail the possibility that BDNF modulates synaptic neurotransmissions by using patch-clamp technique in rat hippocampal CA1 region. BDNF (20 -100 ng/ml) did not show any appreciable effect on evoked EPSCs, but it markedly reduced both evoked and spontaneous IPSCs within 5 min, and the reduction persisted while BDNF was present. BDNF also attenuated GABA A receptor-mediated response to applied GABA. However, BDNF failed to attenuate IPSCs when the postsynaptic pyramidal neuron was loaded intracellularly with 200 nM K252a, an alkaloid that inhibits the kinase activity of Trk receptor family, through the patch pipette. Intracellular application of 200 nM K252b, a weaker inhibitor of Trk-type kinase, did not affect the inhibition. The attenuating effect also was prevented by postsynaptic injection of U73122 (5 M), a broad-spectrum PLC inhibitor, and by strong chelation of intracellular Ca 2ϩ with 10 mM BAPTA. These data suggest that BDNF modulates GABA A synaptic responses by postsynaptic activation of Trk-type receptor and subsequent Ca 2ϩ mobilization in the CNS.Key words: BDNF; GABA A receptor; disinhibition; plasticity; LTP; hippocampus Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. During brain development neurotrophins and their receptors display distinct stage-and tissue-specific patterns of expression (Ernfors et al., 1990a;Phillips et al., 1990;Merlio et al., 1992). BDNF mRNA is observed in the embryonic stage and is still present in the postnatal and adult stages (Ernfors et al., 1990b;Maisonpierre et al., 1990; Freidman et al., 1991). In the adult stage its expression level is modulated dramatically by neuronal activity (Falkenberg et al., 1992;Patterson et al., 1992;Rocamora et al., 1992;Bengzon et al., 1993;Kokaia et al., 1993). Moreover, expression of TrkB, a functional BDNF receptor, not only increases during embryonic development but also continues to increase until several weeks after birth in the hippocampus (Masana et al., 1993;Ringstedt et al., 1993). These observations suggest that in the adult CNS dynamic change in BDNF level still can trigger neuronal plasticity via activation of TrkB. Indeed, neurotrophins are secreted by neurons in both a constitutive and an activity-dependent manner Thoenen, 1995, 1996;Griesbeck et al., 1995;Thoenen, 1995;Goodmann et al., 1996). Additionally, BDNF induces long-lasting enhancement of synaptic transmission (Kang and Schuman, 1995) and facilitates the induction of long-term potentiation (LTP) in the hippocampus (Figurov et al., 1996); however, the site and mechanism of action of BDNF remain unclear, becau...

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“…TrkA is the biologically functional receptor for nerve growth factor (NGF) [9,13], whereas its homolog TrkB binds three different neurotrophins [3,8,16,24,36] namely brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) [5,14,15,31,32]. The extracellular domains of Trk-type receptors harbor a modular mosaic of potential ligand binding modules, namely two immunoglobulin (Ig)-like domains and an LRM3-cassette consisting of a tandem array of three leucine-rich motifs (LRMs) flanked by cysteine-rich clusters [28].…”

Section: Introductionmentioning

confidence: 99%

Specific neurotrophin binding to leucine‐rich motif peptides of TrkA and TrkB

et al. 1995

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trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor

Cited by 784 publications

References 39 publications

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

Inhibition of GABA_ASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus

Specific neurotrophin binding to leucine‐rich motif peptides of TrkA and TrkB

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trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor

Cited by 784 publications

References 39 publications

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

Inhibition of GABAASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus

Specific neurotrophin binding to leucine‐rich motif peptides of TrkA and TrkB

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Inhibition of GABA_ASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus