Experimental Evidence for the Involvement of PDLIM5 in Mood Disorders in Hetero Knockout Mice

<div><p>Background</p><p>Reports indicate that PDLIM5 is involved in mood disorders. The <i>PDLIM5</i> (PDZ and LIM domain 5) gene has been genetically associated with mood disorders; it’s expression is upregulated in the postmortem brains of patients with bipolar disorder and downregulated in the peripheral lymphocytes of patients with major depression. Acute and chronic methamphetamine (METH) administration may model mania and the evolution of mania into psychotic mania or schizophrenia-like behavioral changes, respectively.</p> <p>Methods</p><p>To address whether the downregulation of PDLIM5 protects against manic symptoms and cause susceptibility to depressive symptoms, we evaluated the effects of reduced <i>Pdlim5</i> levels on acute and chronic METH-induced locomotor hyperactivity, prepulse inhibition, and forced swimming by using <i>Pdlim5</i> hetero knockout (KO) mice.</p> <p>Results</p><p>The homozygous KO of <i>Pdlim5</i> is embryonic lethal. The effects of METH administration on locomotor hyperactivity and the impairment of prepulse inhibition were lower in <i>Pdlim5</i> hetero KO mice than in wild-type mice. The transient inhibition of PDLIM5 (achieved by blocking the translocation of protein kinase C epsilon before the METH challenge) had a similar effect on behavior. <i>Pdlim5</i> hetero KO mice showed increased immobility time in the forced swimming test, which was diminished after the chronic administration of imipramine. Chronic METH treatment increased, whereas chronic haloperidol treatment decreased, <i>Pdlim5</i> mRNA levels in the prefrontal cortex. Imipramine increased <i>Pdlim5</i> mRNA levels in the hippocampus.</p> <p>Conclusion</p><p>These findings are partially compatible with reported observations in humans, indicating that PDLIM5 is involved in psychiatric disorders, including mood disorders.</p> </div

Effects of PKCε-TIP on locomotor activity and prepulse inhibition response to METH.

<p>Relative locomotor activity (A, B) and prepulse inhibition (C) by the treatment of PKCε-TIP after chronic METH administration. Values are shown as mean ± SD. P values are based on ANOVA. * p<0.05 and ** p<0.01 by ANOVA.</p

Relative Pdlim5 expression levels after METH, haloperidol and imipramine administrations in mice brains.

<p>Seven-week-old C57BL/6J male mice were treated with an intraperitoneal injection (i.p.) of METH (3.0 mg/kg, once daily for 14 days) (A, B), haloperidol (1 mg/kg, once daily for 49 days) (C), imipramine (20 mg/kg, once daily for 14 days) (D), or vehicle-saline. The upregulated <i>Pdlim5</i> expression in the prefrontal cortex of chronic METH-administered mice (A) was confirmed by a separate experiment using a different mice cohort (B). Values are shown as mean ± SD. * <i>p</i><0.05 and ** <i>p</i><0.01 by Student’s t test.</p

Effect of METH administration on locomotor activity and prepulse inhibition.

<p>Relative locomotor activity and prepulse inhibition after acute (A, B, C) and chronic (D, E, F) administration of METH in <i>Pdlim5</i>+/+ and <i>Pdlim5</i>+/− mice. Values are shown as mean ± SD. * <i>p</i><0.05 and ** <i>p</i><0.01 by ANOVA.</p

Effect of imipramine treatment on forced swimming.

<p>Immobility time of <i>Pdlim5</i> hetero KO and wild-type mice in the forced swimming test with saline or chronic imipramine administration. Values are shown as mean ± SD. * p<0.05 and ** p<0.01 by ANOVA.</p

Generation of Induced Pluripotent Stem Cells from Human Nasal Epithelial Cells Using a Sendai Virus Vector

<div><p>The generation of induced pluripotent stem cells (iPSCs) by introducing reprogramming factors into somatic cells is a promising method for stem cell therapy in regenerative medicine. Therefore, it is desirable to develop a minimally invasive simple method to create iPSCs. In this study, we generated human nasal epithelial cells (HNECs)-derived iPSCs by gene transduction with Sendai virus (SeV) vectors. HNECs can be obtained from subjects in a noninvasive manner, without anesthesia or biopsy. In addition, SeV carries no risk of altering the host genome, which provides an additional level of safety during generation of human iPSCs. The multiplicity of SeV infection ranged from 3 to 4, and the reprogramming efficiency of HNECs was 0.08–0.10%. iPSCs derived from HNECs had global gene expression profiles and epigenetic states consistent with those of human embryonic stem cells. The ease with which HNECs can be obtained, together with their robust reprogramming characteristics, will provide opportunities to investigate disease pathogenesis and molecular mechanisms in vitro, using cells with particular genotypes.</p> </div

Cystatin SN Upregulation in Patients with Seasonal Allergic Rhinitis

<div><p>Seasonal allergic rhinitis (SAR) to the Japanese cedar, <i>Cryptomeria japonica</i> (JC) pollen is an IgE-mediated type I allergy affecting nasal mucosa. However, the molecular events underlying its development remain unclear. We sought to identify SAR-associated altered gene expression in nasal epithelial cells during natural exposure to JC pollen. We recruited study participants in 2009 and 2010 and collected nasal epithelial cells between February and April, which is the period of natural pollen dispersion. Fifteen patients with SAR-JC and 13 control subjects were enrolled in 2009, and 17 SAR-JC patients, 13 sensitized asymptomatic subjects (Sensitized), and 15 control subjects were enrolled in 2010. Total RNA was extracted from nasal epithelial cells and 8 SAR-JC patients and 6 control subjects in 2009 were subjected to microarray analysis with the Illumina HumanRef-8 Expression BeadChip platform. Allergen-stimulated histamine release was examined in the peripheral blood basophils isolated from patients with SAR. We identified 32 genes with significantly altered expression during allergen exposure. One of these, <i>CST1</i> encodes the cysteine protease inhibitor, cystatin SN. <i>CST1</i> expression in nasal epithelial cells was significantly upregulated in both the 2009 and 2010 SAR-JC groups compared with the control groups. Immunohistochemical staining confirmed the increased expression of CST1 in the nasal epithelial cells of SAR patients. Addition of exogenous CST1 to basophils inhibited JC allergen-stimulated histamine release in vitro. We propose that CST1 may contribute to inactivation of protease allergens and help re-establish homeostasis of the nasal membranes.</p></div

GSEA using dataset of the study by Giovannini-Chami [5].

<p>GSEA using dataset of the study by Giovannini-Chami <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067057#pone.0067057-Palmer1" target="_blank">[5]</a>.</p

Histamine release by peripheral basophils stimulated with JC allergen.

<p>Cells were cultured with Cryj1 both in the presence and absence of recombinant CST1. *, P<0.05.</p

Immunohistochemical staining of CST1 in nasal epithelial cells.

<p>Representative immunostaining of CST1 expression inthe nasal epithelium of 2 SAR patients (A and B) and 2 Control subjects (C and D). Magnification:×200.</p