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The Journal of Neuroscience, January 15, 2000, 20(2):771-782

BDNF Promotes the Regenerative Sprouting, But Not Survival, of Injured Serotonergic Axons in the Adult Rat Brain

Laura A. Mamounas¹, C. Anthony Altar², Mary E. Blue³, David R. Kaplan⁴, Lino Tessarollo⁵, and W. Ernest Lyons⁵

¹ Department of Pathology (Division of Neuropathology), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ² Global Neuroscience Research, Otsuka America Pharmaceutical, Rockville, Maryland 20850, ³ The Kennedy-Krieger Research Institute and Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ⁴ Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada, and ⁵ Neural Development Group, Advanced Bioscience Laboratories Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702

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.

Key words: neurotrophin; BDNF; TrkB; serotonin; structural plasticity; sprouting; cerebral cortex; neurotoxicity; amphetamines; p-chloroamphetamine

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Copyright © 2000 Society for Neuroscience  0270-6474/00/202771-12$05.00/0

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