BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain

Laura A. Mamounas, C. Anthony Altar, Mary E Blue, David R. Kaplan, Lino Tessarollo, W. Ernest Lyons

Research output: Contribution to journalArticle

Abstract

Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the adult brain and can prevent the severe loss of cortical 5-HT axons caused by the neurotoxin p-chloroamphetamine (PCA). However, it has not been determined whether BDNF promotes the survival of 5-HT axons during PCA-insult or facilitates their regenerative sprouting after injury. We show here that BDNF fails to protect most 5-HT axons from PCA-induced degeneration. Instead, chronic BDNF infusions markedly stimulate the sprouting of both intact and PCA-lesioned 5-HT axons, leading to a hyperinnervation at the neocortical infusion site. BDNF treatment promoted the regrowth of 5-HT axons when initiated up to a month after PCA administration. The sprouted axons persisted in cortex for at least 5 weeks after terminating exogenous BDNF delivery. BDNF also encouraged the regrowth of the 5-HT plexus in the hippocampus, but only in those lamina where 5-HT axons normally ramify. In addition, intracortical BDNF infusions induced a sustained local activation of the TrkB receptor. The dose-response profiles for BDNF to stimulate 5-HT sprouting and Trk signaling were remarkably similar, suggesting a physiological link between the two events; both responses were maximal at intermediate doses of BDNF but declined at higher doses ('inverted-U-shaped' dose-response curves). Underlying the downregulation of the Trk signal with excessive BDNF was a decline in full- length TrkB protein, but not truncated TrkB protein or TrkB mRNA levels. Thus, BDNF-TrkB signaling does not protect 5-HT neurons from axonal injury, but has a fundamental role in promoting the structural plasticity of these neurons in the adult brain.

Original languageEnglish (US)
Pages (from-to)771-782
Number of pages12
JournalJournal of Neuroscience
Volume20
Issue number2
StatePublished - Jan 15 2000

Fingerprint

Brain-Derived Neurotrophic Factor
Axons
Serotonin
p-Chloroamphetamine
Brain
Neurons
trkB Receptor
Wounds and Injuries
Neurotoxins
Hippocampus
Proteins
Down-Regulation

Keywords

  • Amphetamines
  • BDNF
  • Cerebral cortex
  • Neurotoxicity
  • Neurotrophin
  • P- chloroamphetamine
  • Serotonin
  • Sprouting
  • Structural plasticity
  • TrkB

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mamounas, L. A., Altar, C. A., Blue, M. E., Kaplan, D. R., Tessarollo, L., & Lyons, W. E. (2000). BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. Journal of Neuroscience, 20(2), 771-782.

BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. / Mamounas, Laura A.; Altar, C. Anthony; Blue, Mary E; Kaplan, David R.; Tessarollo, Lino; Lyons, W. Ernest.

In: Journal of Neuroscience, Vol. 20, No. 2, 15.01.2000, p. 771-782.

Research output: Contribution to journalArticle

Mamounas, LA, Altar, CA, Blue, ME, Kaplan, DR, Tessarollo, L & Lyons, WE 2000, 'BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain', Journal of Neuroscience, vol. 20, no. 2, pp. 771-782.
Mamounas, Laura A. ; Altar, C. Anthony ; Blue, Mary E ; Kaplan, David R. ; Tessarollo, Lino ; Lyons, W. Ernest. / BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. In: Journal of Neuroscience. 2000 ; Vol. 20, No. 2. pp. 771-782.
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AU - Altar, C. Anthony

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AU - Kaplan, David R.

AU - Tessarollo, Lino

AU - Lyons, W. Ernest

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AB - Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the adult brain and can prevent the severe loss of cortical 5-HT axons caused by the neurotoxin p-chloroamphetamine (PCA). However, it has not been determined whether BDNF promotes the survival of 5-HT axons during PCA-insult or facilitates their regenerative sprouting after injury. We show here that BDNF fails to protect most 5-HT axons from PCA-induced degeneration. Instead, chronic BDNF infusions markedly stimulate the sprouting of both intact and PCA-lesioned 5-HT axons, leading to a hyperinnervation at the neocortical infusion site. BDNF treatment promoted the regrowth of 5-HT axons when initiated up to a month after PCA administration. The sprouted axons persisted in cortex for at least 5 weeks after terminating exogenous BDNF delivery. BDNF also encouraged the regrowth of the 5-HT plexus in the hippocampus, but only in those lamina where 5-HT axons normally ramify. In addition, intracortical BDNF infusions induced a sustained local activation of the TrkB receptor. The dose-response profiles for BDNF to stimulate 5-HT sprouting and Trk signaling were remarkably similar, suggesting a physiological link between the two events; both responses were maximal at intermediate doses of BDNF but declined at higher doses ('inverted-U-shaped' dose-response curves). Underlying the downregulation of the Trk signal with excessive BDNF was a decline in full- length TrkB protein, but not truncated TrkB protein or TrkB mRNA levels. Thus, BDNF-TrkB signaling does not protect 5-HT neurons from axonal injury, but has a fundamental role in promoting the structural plasticity of these neurons in the adult brain.

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KW - Structural plasticity

KW - TrkB

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