Gender-Dependent Modulation of Brain Monoamines and Anxiety-Like Behaviors in Mice with Genetic Serotonin Transporter and BDNF Deficiencies

Abstract

1. Brain-derived neurotrophic factor (BDNF) supports serotonergic neuronal development and our recent study found that heterozygous mice lacking one BDNF gene allele interbred with male serotonin transporter (SERT) knockout mice had greater reductions in brain tissue serotonin concentrations, greater increases in anxiety-like behaviors and greater ACTH responses to stress than found in the SERT knockout mice alone.2. We investigated here whether there might be gender differences in these consequences of combined SERT and BDNF deficiencies by extending the original studies to female mice, and also to an examination of the effects of ovariectomy and tamoxifen in these female mice, and of 21-day 17-β estradiol implantation in male mice.3. We found that unlike the male SERT × BDNF deficient mice, female SERT × BDNF mice appeared protected by their gender in having significantly lesser reductions in serotonin concentrations in hypothalamus and other brain regions than males, relative to controls. Likewise, in the elevated plus maze, female SERT × BDNF deficient mice demonstrated no increases in the anxiety-like behaviors previously found in males.4. Furthermore, female SERT × BDNF mice did not manifest the ∼ 40% reduction in the expression of TrkB receptors or the ∼ 30% reductions in dopamine and its metabolites that male SERT × BDNF did. After estradiol implantation in male SERT × BDNF mice, hypothalamic serotonin was significantly increased compared to vehicle-implanted mice. These findings support the hypothesis that estrogen may enhance BDNF function via its TrkB receptor, leading to alterations in the serotonin circuits which modulate anxiety-like behaviors.5. This double-mutant mouse model contributes to the knowledge base that will help with understanding gene × gene × gender interactions in studies of SERT and BDNF gene polymorphisms in human genetic disorders such as despression.

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…Furthermore, sb mice exhibit much higher levels of the stress hormone ACTH and increased corticosterone in response to stressful stimuli. Interestingly, male mice have more pronounced deficits than females, and the gender difference could be explained, at least in part, by lower levels of TrkB expression in males (Ren-Patterson et al, 2006). These data support the hypothesis that loss of BDNF expression interacts with serotonin and related circuitry that are involved in modulating anxiogenic behaviors as well as the stress-response machinery.…”

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.…”

“…Male offspring had much greater susceptibility for the more severe phenotype than female mice. 210 Together, these findings of genetic synergy suggest that relatively subtle changes in MECP2 and BDNF function, when combined with alterations in one or more genes in the 5-HT signaling pathway, could accumulate, with detrimental consequences for normal neurodevelopment.…”

“…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.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…121 Interestingly, female gender or oestrogen administration protect against most neurochemical and behavioural effects of the combined 5-HTT/BDNF knock out. 122 In humans, there is a common functional val66met (rs6265) single-nucleotide polymorphism in the translated region, which is part of the pro-BDNF, but not the mature BDNF. The less common met allele (allele frequency 19% in Caucasians and 44% in Asians) is associated with less efficient intracellular pro-BDNF trafficking, impaired activity-dependent BDNF secretion, smaller hippocampal grey matter volume and poor episodic memory.…”