Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice.

To study the neurochemical and behavioral effects of altered brain-derived neurotrophic factor (BDNF) expression on a brain serotonin system with diminished serotonin transport capability, a double-mutant mouse model was developed by interbreeding serotonin transporter (SERT) knockout mice with BDNF heterozygous knockout mice (BDNF +/-), producing SERT -/- x BDNF +/- (sb) mice. Prior evidence implicates serotonin and SERT in anxiety and stress responses. Some studies have shown that BDNF supports serotonergic neuronal development, leading to our hypothesis that reduced BDNF availability during development might exaggerate the consequences of absent SERT function. In the present study, brain serotonin and 5-hydroxyindol acetic acid concentrations in male sb mice were significantly reduced in the hippocampus and hypothalamus compared with wild-type control SB mice, BDNF-deficient Sb mice, and serotonin transporter knockout sB mice. The sb mice had significantly increased anxiety-like behaviors compared with SB, Sb, and sB mice as measured on the elevated plus maze test. These sb mice also had significantly greater increases in plasma adrenocorticotrophic hormone than mice with other genotypes after a stressful stimulus. Analysis of neuronal morphology showed that hypothalamic and hippocampal neurons exhibited 25-30% reductions in dendrites in sb mice compared with SB control mice. These findings support the hypothesis that genetic changes in BDNF expression interact with serotonin and other circuits that modulate anxiety and stress-related behaviors. Thus, this double-mutant mouse model should prove valuable in studying other gene x gene consequences for brain plasticity as well as in evaluating epistatic interactions of BDNF and serotonin transporter gene polymorphisms in neuropsychiatric disorders.