Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities

Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergi c (5-HT) neurons in the central nervous system. However, the role of endoge nous BDNF in the development and function of these neurons has not been est ablished in vivo because of the early postnatal lethality of BDNF null mice . In the present study, we use heterozygous BDNF+/- mice that have a normal life span and show that these animals develop enhanced intermale aggressiv eness and hyperphagia accompanied by significant weight gain in early adult hood; these behavioral abnormalities are known to correlate with 5-HT dysfu nction. Forebrain 5-HT levels and fiber density in BDNF+/- mice are normal at an early age but undergo premature age-associated decrements. However, y oung adult BDNF+/- mice show a blunted c-fos induction by the specific sero tonin releaser-uptake inhibitor dexfenfluramine and alterations in the expr ession of several 5-HT receptors in the cortex, hippocampus, and hypothalam us. The heightened aggressiveness can be ameliorated by the selective serot onin reuptake inhibitor fluoxetine. Our results indicate that endogenous BD NF is critical for the normal development and function of central 5-HT neur ons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF+/- mice may provide a useful model to study human psychiatr ic disorders attributed to dysfunction of serotonergic neurons.