p11 (S100A10), a member of a large family of S100 proteins, interacts with serotonin receptor 1B (5-HTR1B), modulates 5-HT1B receptor signal transduction, and is required for antidepressant responses to activation of this receptor. In the current study, we investigated the specificity of the interaction between 5-HTR1B and p11 by screening brain-expressed S100 proteins against serotonin and noradrenergic receptors. The data indicate that p11 is unique among its family members for its interactions with defined serotonin receptors. We identify a novel p11-interacting receptor (5-HTR4) and characterize the interaction between p11 and 5-HTR4, demonstrating that (1) p11 and 5-HTR4 mRNA and protein are coexpressed in brain regions that are relevant for major depression, (2) p11 increases 5-HTR4 surface expression and facilitates 5-HTR4 signaling, and (3) p11 is required for the behavioral antidepressant responses to 5-HTR4 stimulation in vivo. The essential role played by p11 in modulating signaling through 5-HT4 as well as 5-HT1B receptors supports the concept that this protein may be a key determinant of vulnerability to depression.
The primary action of several antidepressant treatments used in the clinic raises extracellular concentrations of serotonin (5-HT), which subsequently act on multiple 5-HT receptors. The present study examined whether 5-HT 6 receptors might be involved in the antidepressant-like effects mediated by enhanced neurotransmission at 5-HT synapses. A selective 5-HT 6 receptor antagonist, SB271046, was evaluated for its ability to counteract fluoxetine-induced biochemical and behavioral responses in mice. In addition, biochemical and behavioral effects of the 5-HT 6 receptor agonist, 2-ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT), were assessed in mice to ascertain whether enhancement of 5-HT 6 receptor-mediated neurotransmission engenders antidepressant-like effects. SB271046 significantly counteracted the stimulatory actions of fluoxetine on cortical c-fos mRNA, phospho-Ser845-GluR1, and in the tail suspension antidepressant assay, whereas it had no effect on these parameters by itself. EMDT increased the phosphorylation states of Thr -DARPP-32 and Ser 845-GluR1, both in brain slices and in the intact brain, which were effects also seen with the antidepressant fluoxetine; as with fluoxetine, these effects were demonstrated to be independent of D 1 receptor stimulation. Systemic administration of EMDT increased c-fos mRNA expression in the striatum and cerebral cortex and reduced immobility in the tail suspension test. The antidepressant-like effects of EMDT in the tail suspension test were prevented by SB271046. Our results indicate that 5-HT 6 receptor stimulation may be a mechanism initiating some of the biochemical and behavioral outcomes of 5-HT reuptake inhibitors, such as fluoxetine. These findings also indicate that selective 5-HT 6 receptor agonists may represent a novel antidepressant drug class.
Depression is associated with abnormal neuronal plasticity. AMPA receptors mediate transmission and plasticity at excitatory synapses in a manner which is positively regulated by phosphorylation at Ser831-GluR1, a CaMKII/PKC site, and Ser845-GluR1, a PKA site. Treatment with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor fluoxetine increases P-Ser845-GluR1 but not P-Ser831-GluR1. Here, it was found that treatment with another antidepressant, tianeptine, increased P-Ser831-GluR1 in the frontal cortex and the CA3 region of hippocampus and P-Ser845-GluR1 in the CA3 region of hippocampus. A receptorome profile detected no affinity for tianeptine at any monaminergic receptors or transporters, confirming an atypical profile for this compound. Behavioural analyses showed that mice bearing point mutations at both Ser831- and Ser845-GluR1, treated with saline, exhibited increased latency to enter the centre of an open field and increased immobility in the tail-suspension test compared to their wild-type counterparts. Chronic tianeptine treatment increased open-field locomotion and reduced immobility in wild-type mice but not in phosphomutant GluR1 mice. P-Ser133-CREB was reduced in the CA3 region of hippocampus in phosphomutant mice, and tianeptine decreased P-Ser133-CREB in this region in wild-type, but not in phosphomutant, mice. Tianeptine increased P-Ser133-CREB in the CA1 region in wild-type mice but not in phosphomutant GluR1 mice. There were higher basal P-Ser133-CREB and c-fos levels in frontal and cingulate cortex in phosphomutant GluR1 mice; these changes in level were counteracted by tianeptine in a GluR1-independent manner. Using phosphorylation assays and phosphomutant GluR1 mice, this study provides evidence that AMPA receptor phosphorylation mediates certain explorative and antidepressant-like actions under basal conditions and following tianeptine treatment.
P11 (S100A10) has been associated with the pathophysiology of depression both in human and rodent models. Different types of antidepressants have been shown to increase P11 levels in distinct brain regions and P11 gene therapy was recently proven effective in reversing depressive-like behaviours in mice. However, the molecular mechanisms that govern P11 gene expression in response to antidepressants still remain elusive. In this study we report decreased levels of P11, associated with higher DNA methylation in the promoter region, in the prefrontal cortex of the Flinders Sensitive Line (FSL) genetic rodent model of depression. This hypermethylated pattern was reversed to normal, as indicated by the control line, after chronic administration of escitalopram (a selective serotonin reuptake inhibitor; SSRI). The escitalopram-induced hypomethylation was associated with both an increase in P11 gene expression and a reduction in mRNA levels of two DNA methyltransferases that have been shown to maintain DNA methylation in adult forebrain neurons (Dnmt1 and Dnmt3a). In conclusion, our data further support a role for P11 in depression-like states and suggest that this gene is controlled by epigenetic mechanisms that can be affected by antidepressant treatment.
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