Depression research: where are we now?

Extensive studies have led to a variety of hypotheses for the molecular basis of depression and related mood disorders, but a definite pathogenic mechanism has yet to be defined. The monoamine hypothesis, in conjunction with the efficacy of antidepressants targeting monoamine systems, has long been the central topic of depression research. While it is widely embraced that the initiation of antidepressant efficacy may involve acute changes in monoamine systems, apparently, the focus of current research is moving toward molecular mechanisms that underlie long-lasting downstream changes in the brain after chronic antidepressant treatment, thereby reaching for a detailed view of the pathophysiology of depression and related mood disorders. In this minireview, we briefly summarize major themes in current approaches to understanding mood disorders focusing on molecular views of depression and antidepressant action

A novel NDEL1 phosphorylation mediated by TARA-GSK3B complex regulates neuronal development

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Valproate alters dopamine signaling in association with induction of Par-4 protein expression.

Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA), a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC) inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4), an intracellular binding partner of dopamine D2 receptors (DRD2), plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism

Disrupted-in-schizophrenia 1 enhances the quality of circadian rhythm by stabilizing BMAL1

Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that has been implicated in multiple mental disorders. DISC1 is known to regulate neuronal proliferation, signaling, and intracellular calcium homeostasis, as well as neurodevelopment. Although DISC1 was linked to sleep-associated behaviors, whether DISC1 functions in the circadian rhythm has not been determined yet. In this work, we revealed that Disc1 expression exhibits daily oscillating pattern and is regulated by binding of circadian locomotor output cycles kaput (CLOCK) and Brain and muscle Arnt-like protein-1 (BMAL1) heterodimer to E-box sequences in its promoter. Interestingly, Disc1 deficiency increases the ubiquitination of BMAL1 and de-stabilizes it, thereby reducing its protein levels. DISC1 inhibits the activity of GSK3 beta, which promotes BMAL1 ubiquitination, suggesting that DISC1 regulates BMAL1 stability by inhibiting its ubiquitination. Moreover, Disc1-deficient cells and mice show reduced expression of other circadian genes. Finally, Disc1-LI (Disc1 knockout) mice exhibit damped circadian physiology and behaviors. Collectively, these findings demonstrate that the oscillation of DISC1 expression is under the control of CLOCK and BMAL1, and that DISC1 contributes to the core circadian system by regulating BMAL1 stability.11Nsciescopu

Induction of Par-4 expression by chronic VPA treatment.

<p>Time-dependent induction of Par-4 protein in primary cultured neurons. Cultured hippocampal and striatal neurons (DIV 7) were treated with 1 mM VPA. Par-4 protein levels relative to α-tubulin were analyzed by western blot (a) and subject to densitometric analysis (b). Error bars are mean ± SEM values (n = 4; *p<0.05, **p<0.01, ***p<0.001; One-way ANOVA with Bonferroni post hoc test). A. Dose-dependent increase of Par-4 proteins in mouse primary cultured neurons. Cultured primary neurons (DIV 7) were incubated with VPA at doses indicated for 24 hrs, and the Par-4 expression levels were analyzed as in (a). Par-4 levels relative to α-tubulin were analyzed (b). Error bars are mean ± SEM (n = 4; *p<0.05, **p<0.01, ***p<0.001; One-way ANOVA with Bonferroni post hoc test). B. Increased Par-4 mRNA after VPA treatment. Cultured hippocampal neurons (DIV 7) were treated with 1 mM VPA. Fold inductions of Par-4 mRNA relative to GAPDH were assessed by quantitative real-time PCR. Error bars represent mean ± SEM (n = 4; *p<0.05, **p<0.01, ***p<0.001; One-way ANOVA with Bonferroni post hoc test).</p

VPA-induced histone modifications at the Par-4 promoter region.

<p>A. Increased acetylation of histone H3 and H4 at the Par-4 promoter region in a time-dependent manner. Hippocampal neurons (DIV 7) were incubated with 1 mM VPA for 24 hrs and subjected to chromatin immunoprecipitation (ChIP) assay (a). Fold changes in ac-H3 and ac-H4 at the Par-4 promoter regions are shown in (b) relative to control. Error bars are mean ± SEM (n = 4; *p<0.05, **p<0.01, ***p<0.001; One-way ANOVA with Bonferroni post hoc test). B. Dose-dependent increases in ac-H3 and ac-H4 after chronic VPA treatment. Hippocampal neurons (DIV 7) were treated with increasing concentrations of VPA for 24 hrs and subject to ChIP assay (a). Relative fold changes in ac-H3 and ac-H4 at the Par-4 promoter regions were normalized to GAPDH levels (b). Error bars are mean ± SEM (n = 4; *p<0.05, **p<0.01, ***p<0.001; One-way ANOVA with Bonferroni post hoc test).</p