Simultaneous analysis of serotonin transporter, tryptophan hydroxylase 1 and 2 gene expression in the ventral prefrontal cortex of suicide victims

Abstract

Serotonergic signaling abnormalities have been implicated in suicide. Tryptophan hydroxylase (TPH), the rate limiting enzyme of serotonin biosynthesis and the serotonin transporter (SLC6A4), involved in the reuptake of serotonin from the synaptic gap, play major role in serotonergic signaling. In this study, we aimed to compare the levels of expression of these serotonin-related genes between suicide completers and controls and to identify genetic loci involved in their regulation. SLC6A4, TPH1, and TPH2 mRNA levels were measured in the ventral prefrontal cortex (VPFC) of 39 suicide completers and 40 matched controls. To identify the molecular basis of gene expression variation, we performed association studies between cis-acting polymorphisms and SLC6A4, TPH1, and TPH2 transcript levels. Finally, association analyses were carried out between suicide and TPH2 cis-single nucleotide polymorphisms (SNPs) in cohorts of 154 suicide completers and 289 control subjects. Whereas SLC6A4 and TPH1 mRNA expression levels did not differ between suicides and controls, TPH2 levels were found significantly increased (P = 0.003) in suicide completers. We observed that SNP rs10748185 located in the promoter region of TPH2 significantly affect levels of TPH2 mRNA expression. However, we did not find positive association between this eQTL (rs10748185) and suicide. Here, we report the simultaneous analysis of the expression of three serotonin-related genes in the VPFC of suicide victims and controls. This study showed that TPH2 expression levels were increased in the VPFC of suicide victims. Although, we identified a genetic variant that explains variance in TPH2 expression, we did not find evidence associating this cis-regulatory SNP with suicidal behavior.

Recent molecular genetic studies and methodological issues in suicide research

“…This finding is in line with a recent report that measured TPH2 mRNA levels in the ventral prefrontal cortex (VPFC) of 39 suicide completers and forty matched controls, showing increased TPH2 expression levels in suicide victims (Perroud et al, 2010). Another study demonstrated no difference in the postmortem brain gene expression of TPH2 between the suicide group and the non-suicide group (De Luca et al, 2006a).…”

“…Zill et al (2009) found no difference in TPH1 mRNA levels in the cortex of suicide victims compared with the controls. Similarly, Perroud et al (2010) found no difference in the postmortem brain gene expression of TPH1 in VPFC between the suicide group and the non-suicide group.…”

Associations among within-litter differences in early mothering received and later emotional behaviors, mothering, and cortical tryptophan hydroxylase-2 expression in female laboratory rats

“…TPH2 is found in all serotonergic somata and proximal axons (Donner ff Handa 2009;Hale, Shekhar, and Lowry, 2011;Walther, 2003) and its levels are highly correlated with the amount of serotonin that the cells produce and their rate of activity (Calcagno et al, 2007;Cervo et al, 2005;Gutknecht et al, 2012;Patel et al 2004;Zhang et al, 2004). TPH2 mRNA and protein also exist in the cytoplasm of serotonergic terminals, including the prefrontal cortex (Carkaci-Salli et al, 2011;Sakowski et al, 2006;Perroud et al, 2010;Zill et al, 2007). This distal expression in the rat brain overlaps with serotonin immunoreactivity (Cohen et al, 1995;Weissmann et al, 1987), correlates with the local extracellular serotonin release (Calcagno et al, 2007;Chen and Miller, 2012), and for many years has also been suggested to indicate the capacity for local serotonin synthesis (Pickel, 1976;Weissmann et al, 1987;Perroud et al, 2010).…”

“…TPH2 mRNA and protein also exist in the cytoplasm of serotonergic terminals, including the prefrontal cortex (Carkaci-Salli et al, 2011;Sakowski et al, 2006;Perroud et al, 2010;Zill et al, 2007). This distal expression in the rat brain overlaps with serotonin immunoreactivity (Cohen et al, 1995;Weissmann et al, 1987), correlates with the local extracellular serotonin release (Calcagno et al, 2007;Chen and Miller, 2012), and for many years has also been suggested to indicate the capacity for local serotonin synthesis (Pickel, 1976;Weissmann et al, 1987;Perroud et al, 2010). Central serotonin systems are tremendously sensitive to developmental events in male rodents (reviewed in: Albert, VahidAnsari, and Luckhart, 2014), are implicated in the display of maternal behaviors in female rats (Barofsky et al, 1983;Pawluski et al, 2012;Zhao and Li, 2010), and when released in the mPFC is associated with anxiety-related behaviors (see Albert, Vahid-Ansari, and Luckhart, ).…”

Suicide in Children and Adolescents

“…In an association analysis of 154 suicide completers and 289 control subjects, Perroud et al found tryptophan hydroxylase-2 gene expression levels to be increased in ventral prefrontal cortex of suicide victims. [45] …”