BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain.
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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Department of Pathology (Division of Neuropathology), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. Mamounas@welchkink.welch.jhu.edu
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D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D010133:p-Chloroamphetamine / Q000633:toxicity*
D019208:Brain-Derived Neurotrophic Factor; D009498:Neurotoxins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012701:Serotonin; D010133:p-Chloroamphetamine; D020917:Receptor, trkA; D020813:Receptor, trkB