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

TLDR

BDNF supports serotonergic neurons, but its in vivo role has been unclear because BDNF‑null mice die early. The study used heterozygous BDNF⁺/⁻ mice to test whether reduced BDNF levels lead to behavioral and serotonergic abnormalities. Heterozygous BDNF⁺/⁻ mice show early‑adult aggression, hyperphagia, and weight gain, with premature declines in forebrain serotonin, blunted c‑fos induction to dexfenfluramine, altered 5‑HT receptor expression, and fluoxetine‑responsive aggression, underscoring BDNF’s essential role in serotonergic neuron development and behavior and positioning these mice as a model for psychiatric disorders linked to serotonin dysfunction.

Abstract

Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established 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 aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF +/− mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF +/− mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF +/− mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.