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 serotonergi c (5-HT) neurons in the adult brain and can prevent the severe loss of cort ical 5-HT axons caused by the neurotoxin p-chloroamphetamine (PCA). However , it has not been determined whether BDNF promotes the survival of 5-HT axo ns during PCA-insult or facilitates their regenerative sprouting after inju ry. We show here that BDNF fails to protect most 5-HT axons from PCA-induce d degeneration. Instead, chronic BDNF infusions markedly stimulate the spro uting of both intact and PCA-lesioned 5-HT axons, leading to a hyperinnerva tion at the neocortical infusion site. BDNF treatment promoted the regrowth of 5-HT axons when initiated up to a month after PCA administration. The s prouted axons persisted in cortex for at least 5 weeks after terminating ex ogenous 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 ram ify. In addition, intracortical BDNF infusions induced a sustained local ac tivation of the TrkB receptor. The dose-response profiles for BDNF to stimu late 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 wi th excessive BDNF was a decline in full-length TrkB protein, but not trunca ted TrkB protein or TrkB mRNA levels. Thus, BDNF-TrkB signaling does not pr otect 5-HT neurons from axonal injury, but has a fundamental role in promot ing the structural plasticity of these neurons in the adult brain.