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

Abstract

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.

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

“…Superficially, it can be acknowledged that the OCD probands in our study had more L A and fewer L G alleles than the controls and thus were in accord with the direction of the findings of the study by Hu et al (2006); these differences, however, were minute and far from statistically significant. Finally, on the basis of emerging evidence from human (Kaufman et al, 2006) and mouse behavior genetics (Ren-Patterson et al, 2005) that points toward gene  gene interactions of SLC6A4 and BDNF, we investigated combined genotypes for these two genes but found no support for a combined, epistatic involvement of these two genes considered together in OCD (Supplementary Table 2). …”

Advances in behavioral genetics: mouse models of autism

“…134,201,202 Reduction in the levels of Bdnf exacerbates the phenotype of both the Rett syndrome-model mouse 346 and the Sert deletion line. [208][209][210] In the Rett syndrome-model mouse, Bdnf overexpression with an inducible Bdnf transgene leads to partial correction of abnormalities linked to loss of Mecp2 function. 346 As discussed previously, suppressing inhibitory CaMKII phosphorylation through genetic mutation in the mouse model of AS can fully or partially normalize components of the aberrant phenotype.…”

“…Interestingly, heterozygous mice with one null Bdnf allele have decreased function of the serotonin transporter in hippocampus. 195,197 Murphy et al, [208][209][210] in a series of informative studies on gene interactions, showed that deficits in Sert nulls were exacerbated when mice were bred with Bdnf heterozygous animals. Male offspring had much greater susceptibility for the more severe phenotype than female mice.…”

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…This idea was addressed using a double-mutant mouse model (termed sb mice) with one functional allele of BDNF (BDNF + /À) and no functional copies of the 5-HTT (5HTTÀ/À). Loss of BDNF appears to exacerbate brain monoamine deficiencies and increases stress abnormalities observed in 5-HTTÀ/À mice (Ren-Patterson et al, 2005). Compared with either wild-type, BDNF + /À or 5HTTÀ/À mice, the sb mice exhibit lower levels of 5-HT in the hippocampus and hypothalamus, impaired dendritic morphology, and increased anxiogenic behavior.…”