Early life stress and serotonin transporter gene variation interact to affect the transcription of the glucocorticoid and mineralocorticoid receptors, and the co-chaperone FKBP5, in the adult rat brain

Abstract

The short allelic variant of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) has been associated with the etiology of major depression by interaction with early life stress (ELS). A frequently observed endophenotype in depression is the abnormal regulation of levels of stress hormones such as glucocorticoids. It is hypothesized that altered central glucocorticoid influence on stress-related behavior and memory processes could underlie the depressogenic interaction of 5-HTTLPR and ELS. One possible mechanism could be the altered expression of the genes encoding the glucocorticoid and mineralocorticoid receptors (GR, MR) and their inhibitory regulator FK506-binding protein 51 (FKBP5) in stress-related forebrain areas. To test this notion, we exposed heterozygous (5-HTT+/−) and homozygous (5-HTT−/−) serotonin transporter knockout rats and their wildtype littermates (5-HTT+/+) to daily 3 h maternal separations from postnatal day 2 to 14. In the medial prefrontal cortex (mPFC) and hippocampus of the adult male offspring, we found that GR, MR, and FKBP5 mRNA levels were affected by ELS × 5-HTT genotype interaction. Specifically, 5-HTT+/+ rats exposed to ELS showed decreased GR and FKBP5 mRNA in the dorsal and ventral mPFC, respectively. In contrast, 5-HTT+/− rats showed increased MR mRNA levels in the hippocampus and 5-HTT−/− rats showed increased FKBP5 mRNA in the ventral mPFC after ELS exposure. These findings indicate that 5-HTT genotype determines the specific adaptation of GR, MR, and FKBP5 expression in response to early life adversity. Therefore, altered extra-hypothalamic glucocorticoid signaling should be considered to play a role in the depressogenic interaction of ELS and 5-HTTLPR.

Both maternal care received and genotype influence stress‐related phenotype in female rats

“…However, genotypic variation did not replicate in Study 2, though genetic variation in 5htt was also associated with differential levels of USVs in early life, and differential levels of locomotor activity in adulthood. These results are perhaps not surprising given that 5htt genotype has been shown to affect GR, MR, FKBP5 activity as well as DNA methylation in the CRF gene, all thought to underlie the expression of anxiety behavior (van der Doelen, Calabrese, et al, ; van der Doelen, Deschamps, et al, ; ). Taken together, our findings suggest that the influence of higher levels of maternal care received on offspring anxiety behavior from early life throughout adulthood depend upon 5htt genotype.…”

“…Overall, the rationale behind the choice of a focus on 5htt, Nr3c1, and Fkbp5 genes in the same samples is strengthened by the findings that 5htt gene variation is known to interact with early life stress and adversity, and associates with altered transcription of GR receptors, its co-chaperone FKBP5 (van der Doelen, Calabrese, et al, 2014), plasma levels of CORT, mRNA levels of adrenocorticotropin receptor (van der Doelen, Calabrese, et al, 2014), and DNA methylation of the corticotropin-releasing factor gene (van der Doelen et al., 2015) in rats.…”

Interplay between stress response genes associated with attention‐deficit hyperactivity disorder and brain volume

“…The three-way interaction analysis indicated that carrying the 9 haplotype only strengthened the association between stress exposure and ADHD severity for L-allele homozygotes. Both animal and human studies have provided evidence of an inverse relation between 5-HTT and NR3C1 expression (Duman & Canli 2015;van der Doelen et al 2014). One study has also directly investigated variation in these two genes together, and reported that individuals carrying both the 5-HTTLPR S-allele and the NR3C1 Bcl1 C-allele displayed higher cortisol reactivity in response to stress (Taylor et al 2014).…”

“…A meta-analysis has established that the 5-HTTLPR S-allele is associated with higher cortisol levels in response to acute stressors than the L-allele (Miller et al 2013), a difference further strengthened by long-term stress exposure (Alexander et al 2009). Administration of dexamethasone, a GR-specific glucocorticoid, increases 5-HTT expression (Glatz et al 2003), and genetically conveyed high 5-HTT availability is associated with lower NR3C1 expression after stress exposure in rats (van der Doelen et al 2014). These findings suggest the presence of a feedback loop between the GR and 5-HTT, raising the possibility that genetic variation in NR3C1 and 5-HTT may moderate each other's effects on the brain's stress response.…”

The Serotonin Transporter and Early Life Stress: Translational Perspectives

“…The basal level (non-stressed) of SERT +/− rodents were compared with the basal level of SERT +/+ rodents (C). The data from ELS groups were compared with the basal levels in same genotype animals .# , Low vs. high maternal care in mice .* , these studies all included SERT −/− rats to determine an interaction effect .1, Calabrese et al (2015);2, Carola et al (2008);3, Carola et al (2011);4, van der Doelen et al (2014b);5, van der Doelen et al (2015);6 , van der Doelen et al (2017) .…”