FUNCTIONAL EVIDENCE THAT BDNF IS AN ANTEROGRADE NEURONAL TROPHIC FACTOR IN THE CNS

In this report, we have tested the hypothesis that brain-derived neuro trophic factor (BDNF) is an anterograde neurotrophic factor in the CNS and have focused on central noradrenergic neurons that synthesize BDN F. Double-label immunocytochemistry for BDNF and dopamine-beta-hydroxy lase (DBH), a marker for noradrenergic neurons, demonstrated that BDNF is partially localized to noradrenergic nerve fibers and terminals in the adult rat brain. To test the functional importance of this antero grade BDNF, we analyzed transgenic mice carrying a DBH-BDNF minigene. Increased synthesis of BDNF in noradrenergic neurons of DBH-BDNF mice caused elevated TrkB tyrosine kinase activation throughout postnatal l ife in the neocortex, a noradrenergic target region. This afferently r egulated increase in TrkB receptor activity led to long-lasting altera tions in cortical morphology. To determine whether noradrenergic neuro n-expressed BDNF also anterogradely regulated neuronal survival, we ex amined a second noradrenergic target, neonatal facial motoneurons. One week after axotomy, 72% of facial motoneurons were lost in control an imals, whereas only 30-35% were lost in DBH-BDNF transgenic mice. Alto gether, these results indicate that BDNF is anterogradely transported to fibers and terminals of noradrenergic neurons, that anterogradely s ecreted BDNF causes activation of TrkB in target regions, and that thi s secretion has functional consequences for target neuron survival and differentiation. This presynaptic secretion of BDNF may provide a cel lular mechanism for modulating neural circuitry, in either the develop ing or mature nervous system.