The activin system is a target of chronic paroxetine treatment
Chronic antidepressant treatment with paroxetine significantly increased activin βA mRNA expression in the CA1 (P<0.05) and the dentate gyrus (P<0.05; ). Paroxetine treatment had no effect on activin βA mRNA level in the CA3 area of the hippocampus, the cortex and the thalamus (data not shown).
Figure 1 The activin system is a target of chronic treatment with the antidepressant paroxetine. (a) Chronic paroxetine treatment significantly increases the expression of activin βA mRNA in the CA1 region of the hippocampal pyramidal cell layer (CA1) (more ...)
Activin is composed of homodimers or heterodimers of the β-subunits (for example, activin A is a homodimer consisting of two activin βA subunits), whereas inhibin is a dimeric protein composed of an α- and β-subunit. To exclude the possibility that the upregulation of activin βA might lead to increased formation of inhibin A, which is a heterodimer consisting of an inhibin α and an activin βA subunit, in situ hybridization for the inhibin α subunit was performed. Chronic paroxetine treatment resulted in a significant decrease of inhibin α mRNA levels in the dentate gyrus (P<0.05), whereas no effects of paroxetine on inhibin α mRNA levels could be observed in the CA1 and the CA3 region of the hippocampus or the cortex (). These results indicate that activin A, but not inhibin A, is a target of paroxetine-induced upregulation.
For activin receptor IA mRNA, a significant upregulation following chronic paroxetine treatment was observed in the hippocampal dentate gyrus as well as the CA3 region of the pyramidal cell layer (P<0.05; ).
Subchronic, but not acute treatment with paroxetine increases activin βA mRNA levels in the hippocampal dentate gyrus
Acute paroxetine treatment had no significant effect on activin βA mRNA expression levels in any of the regions investigated (). In contrast, subchronic treatment with paroxetine already resulted in an increase of activin βA mRNA levels in the CA1 and the dentate gyrus of the hippocampus (P<0.05). In the hippocampal CA3 region, a downregulation of activin βA mRNA was observed (P<0.05) ().
Figure 2 Regulation of hippocampal activin βA mRNA expression is dependent on the duration of paroxetine treatment. (a) Acute treatment with paroxetine did not alter the expression level of activin βA mRNA in any of the neuroantomical regions examined (more ...)
Stereotactic injection of activin A does not alter basal locomotor behaviour in the modified holeboard test
Injection of activin A bilaterally into either the amygdala or the dentate gyrus did not significantly alter any of the behavioural parameters scored in the modified holeboard test; in particular, there was no difference in general locomotor activity (total distance travelled) during 5
min of holeboard exposure (amygdala
: vehicle, 17.12±3.3; activin A, 22.62±3.0; dentate gyrus
: vehicle, 21.4±7.4; activin A, 24.5±6.1).
Stereotactic injection of activin A into the hippocampal dentate gyrus exerts region-specific antidepressant-like effects in the Porsolt FST
We observed a pronounced antidepressant-like effect of activin A injection into the dentate gyrus in the FST: animals treated with activin A showed an increase in struggling (P
<0.05) and a significant decrease in floating behaviour (P
<0.01) with no change in swimming () 15
min after treatment. The significant difference in struggling behaviour between the treatment groups could still be observed when animals were retested 24
h after activin A injection (P
Figure 3 Stereotactic infusion of activin A into the hippocampal dentate gyrus exerts antidepressant-like behavioural effects in the forced swim test (FST) paradigm. (a) A strong antidepressant-like effect of activin A injection into the hippocampal dentate gyrus (more ...)
Acute injection of activin A into the amygdala did not significantly alter any of the behavioural parameters measured in the FST (). At the retest 24
h after the activin A injection, we observed a trend (P
=0.056) towards an increase in swimming behaviour in animals that had been injected with activin A into the amygdala compared with vehicle-injected animals with no effect on struggling or floating ().
Genetic variants in betaglycan, a member of the human activin system, predict antidepressant treatment response in depression
From 575 enroled depressed patients, 329 achieved response after 5 weeks of antidepressant treatment and 246 were non-responders. In all, 166 SNPs within 10 genes belonging to the activin signalling pathway were selected for association with treatment response. rs12082710 genotype, lying within the betaglycan gene (TGFBR3), achieved the best association with a nominal allelic P-value of 0.0003 and survived correction for multiple testing with an adjusted P-value of 0.044, odds ratio of 0.65, confidence interval of 0.51–0.82 (see for regional association plot of TGFBR3). We re-run PLINK using age, gender and severity of depression at admission as covariate, but observed no significant alteration of the association with response. The homozygote carriers of the major allele were more frequent among responders (responders vs non-responders: TT=43.8%/26.8%). A repeated-measures ANOVA showed a highly significant interaction between rs12082710 genotype (F926,608=4.8; P=9.28 × 10–5) and time on change in HAM-D score. There was also a significant main effect of rs12082710 genotype (F2819,316=6.7; P=0.001) (see ). When adding age and gender as a covariate in this repeated-measures analysis, the associations with the SNP remained significant (interaction effect: F926,608=5.042; P=1.97 × 10–5). Since the severity of depression measured at admission is already a dependent variable of the ANOVA, it was not used as a covariate.
Figure 4 Association of single-nucleotide polymorphisms (SNPs) in TGFBR3 and response to antidepressant treatment. The –logP-values, allelewise (y axis), are plotted against physical location of the SNPs on chromosome 1 (x axis). Two red markers: (more ...)
Figure 5 Genetic association study: association of TGFBR3 SNP rs12082710 genotype with response over 5 weeks treatment with antidepressants after admission to hospital. Hamilton Depression Rating Scale (HAM-D) scores over the first 5 weeks of hospitalization plotted (more ...)
Overall 14 SNPs were nominally associated with treatment response after 5 weeks, 9 of these were located within TGFBR3, but only two of these in strong linkage disequilibrium (r2 >0.8; see ).