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-beta estradiol implantation to male mice. 3. We found that unlike the male SERTxBDNF-deficient mice, female SERTxBDNF 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 SERTxBDNF-deficient mice demonstrated no increases in the anxiety-like behaviors previously found in males. 4. Furthermore, female SERTxBDNF mice did not manifest the approximately 40% reduction in the expression of TrkB receptors or the approximately 30% reductions in dopamine and its metabolites that male SERTxBDNF did. After estradiol implantation in male SERTxBDNF 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 in understanding genexgenexgender interactions in studies of SERT and BDNF gene polymorphisms in human genetic diseases such as anxiety disorders and depression.

Sex differences in brain‐derived neurotrophic factor signaling and functions

“…In contrast to the depression behavior, heterozygous depletion of BDNF gene ( BDNF+/− ) alleviates the anxiety behavior only in female serotonin transporter knockout (SERT−/−) mice (Ren-Patterson et al 2006). This study reveals that female SERT−/−BDNF+/− mice have higher serotonin (5-HT) and its metabolites 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus and hypothalamus, elevated catecholamines [dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid] in striatum, and augmented hypothalamic TrkB expression than SERT−/−BDNF+/ + mice.…”

Aging and estradiol effects on gene expression in the medial preoptic area, bed nucleus of the stria terminalis, and posterodorsal medial amygdala of male rats

“…There is also strong evidence for estradiol regulation of BDNF in the female brain, including in hypothalamic regions (Yin et al, 2015, Zhu et al, 2013). While sex differences in expression of BNDF were reported in hippocampus (Franklin and Perrot-Sinal, 2006), this was not found in the hypothalamus of mice (Ren-Patterson et al, 2006). …”

Distribution of Phosphorylated TrkB Receptor in the Mouse Hippocampal Formation Depends on Sex and Estrous Cycle Stage

“…The behavioral effects of BDNF reduction in mice differ significantly in males and females, and some of these differences can be explained by the presence or absence of estradiol (Monteggia et al, 2006; Ren-Patterson et al, 2006). In keeping with this idea, hippocampal BDNF expression is low in males and low-estradiol females, compared to proestrus females (Scharfman et al, 2003).…”