Mood-stabilizers differentially affect housekeeping gene expression in human cells.

Recent studies have revealed that antidepressants affect the expression of constitutively expressed "housekeeping genes" commonly used as normalizing reference genes in quantitative polymerase chain reaction (qPCR) experiments. There has yet to be an investigation however on the effects of mood-stabilizers on housekeeping gene stability. The current study utilized lymphoblastoid cell lines (LCLs) derived from patients with mood disorders to investigate the effects of a range of doses of lithium (0, 1, 2 and 5 mM) and sodium valproate (0, 0.

Putative transcriptomic biomarkers in the inflammatory cytokine pathway differentiate major depressive disorder patients from control subjects and bipolar disorder patients.

Mood disorders consist of two etiologically related, but distinctly treated illnesses, major depressive disorder (MDD) and bipolar disorder (BPD). These disorders share similarities in their clinical presentation, and thus show high rates of misdiagnosis. Recent research has revealed significant transcriptional differences within the inflammatory cytokine pathway between MDD patients and controls, and between BPD patients and controls, suggesting this pathway may possess important biomarker properties.

Allele-specific expression of the serotonin transporter and its transcription factors following lamotrigine treatment in vitro.

Lamotrigine, a mood stabilizer used clinically in the treatment of bipolar disorder, is thought to exert actions on the serotonin system. However lamotrigine's exact mechanism of action remains unclear. The current study investigated whether lamotrigine might exert its effects through altering the expression of the serotonin transporter (5-HTT) gene and its regulatory transcription factors Y box binding protein 1 (YB-1) and CCCTC-binding factor (CTCF).

ATP-binding cassette sub-family F member 1 (ABCF1) is identified as a putative therapeutic target of escitalopram in the inflammatory cytokine pathway.

The inflammatory cytokine pathway may be a potential therapeutic target for major depressive disorder (MDD). Previous reports suggest that antidepressants have anti-inflammatory properties and can cause a reduction in proinflammatory cytokines. Recent evidence suggests this might be mediated at the level of the transcriptome.

Tumor necrosis factor and its targets in the inflammatory cytokine pathway are identified as putative transcriptomic biomarkers for escitalopram response.

Converging evidence suggests that the activation of the inflammatory cytokine pathway is important in the pathophysiology of unipolar depression. Antidepressants have anti-inflammatory properties and evidence suggests that inter-individual variability in response to antidepressants may reflect genetic differences in the inflammatory cytokine pathway. In particular, protein levels of Tumor Necrosis Factor (TNF) and the SNPs rs1126757 in interleukin-11 (IL11), and rs7801617 in interleukin-6 (IL6), have previously been implicated in the clinical response to the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram.

Genes within the serotonergic system are differentially expressed in human brain.

Background: Serotonin is an important neurotransmitter with wide-ranging functions throughout the central nervous system. There is strong evidence to suggest that regulation of serotonergic gene expression might be related to genetic variability, and several studies have focused on understanding the functional effects of specific polymorphisms within these genes on expression levels. However, the combination of genotype together with gender and brain region could have an overall effect on gene expression.

Functional genetic polymorphisms in serotonin and dopamine gene systems and their significance in behavioural disorders.

Many genes in the monoamine neurotransmitter pathways possess functional variants which have been associated with human behavioural disorders and traits, making them of important clinical relevance. In this chapter, we summarize the most recent literature concerning functional studies on these variants and their possible behavioural consequences. Such studies have adopted a variety of strategies.

Relationship between VNTR polymorphisms of the human dopamine transporter gene and expression in post-mortem midbrain tissue.

Attention deficit hyperactivity disorder (ADHD) is currently one of the most prevalent childhood behavioral disorders. The disorder is found to be highly heritable, suggesting a large genetic component. Association studies have repeatedly implicated the dopamine transporter (DAT1) gene, and in particular the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism located in the 3'UTR of the gene.

Functional polymorphisms in dopamine and serotonin pathway genes.

There is mounting evidence on the functional significance of single nucleotide and simple repeat sequence polymorphisms in both the coding and regulatory regions of genes in the monoamine neurotransmitter pathways. Many of these gene variants have been associated with human behavioral disorders and traits, and thus have important clinical relevance. This review summarizes the literature on the published functional studies from a molecular, cellular, and neurobiological perspective, and notes their possible behavioral consequences.

Transient expression analysis of allelic variants of a VNTR in the dopamine transporter gene (DAT1).

Background: The 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the dopamine transporter gene (DAT1) has been associated with a range of psychiatric phenotypes, most notably attention-deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study we have characterised the genomic structure of the 9- and 10-repeat VNTR alleles, and directly examined the role of the polymorphism in mediating gene expression by measuring comparative in vitro cellular expression using a reporter-gene assay system.

Functional effects of a tandem duplication polymorphism in the 5'flanking region of the DRD4 gene.

Background: Several polymorphisms have been identified in the 5'flanking region of the human dopamine D(4) receptor gene (DRD4), including a tandem duplication polymorphism. This comprises a 120-base-pair repeat sequence that is known to have different allele frequencies in various populations around the world. Furthermore, various studies have revealed evidence of linkage to attention-deficit/hyperactivity disorder and association with schizophrenia and methamphetamine abuse.

The -1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity.

Background: The -1438A/G single nucleotide polymorphism (SNP) lies just upstream of two alternative promoters for the 5-hydroxytryptamine type 2A (5-HT2A) receptor gene (HTR2A) and is in strong linkage disequilibrium with the 102T/C SNP. Both SNPs are associated with numerous psychiatric disorders and related phenotypes. A possible functional affect of the -1438A/G SNP might underlie associations of both linked SNPs with these neuropsychiatric disorders.

From transcriptional regulation to aggressive behavior.

Gene expression in higher organisms, is, to a large degree, controlled at the level of transcription, where DNA-binding proteins (transcription factors) play an influential role in gene regulation. This is achieved through various mechanisms, including those that involve silencer and enhancer regions. Variation in those regulatory regions, as well as in the genes encoding the transcription factors, has been shown to generate functional effects at the molecular, cellular, and neurobehavioral levels.

Developmental expression of the zinc finger transcription factor DRRF (dopamine receptor regulating factor).

Dopamine receptor regulating factor (DRRF) is a novel transcription factor with unique anatomical distribution and functional properties, suggesting its importance in regulating dopaminergic neurotransmission. To gain insight into the in vivo function of this factor during embryogenesis, we studied its distribution at embryonic days E8-E16 in the mouse using in situ hybridization. DRRF mRNA is expressed uniquely during development at all time points tested with high levels observed at E12, E14 and E16 in various tissues.