Dong Hoon Oh

Neuropathological abnormalities of astrocytes, GABAergic neurons, and pyramidal neurons in the dorsolateral prefrontal cortices of patients with major depressive disorder.

Human post-mortem brain studies have revealed reduced density and size of neurons and glial cells in the dorsolateral prefrontal cortex (dlPFC) in major depressive disorder (MDD). However, the basis of these cytoarchitectural abnormalities and the relationship between them are not understood. We hypothesized that the reduced density of GABAergic neurons and glial cells was associated with altered glutamate neurotransmission in the dlPFC. In order to test this hypothesis, we examined a specific marker type (i.e., calretinin, CR: as a marker of GABAergic neurons) and also attempted to identify the neuropathological markers that correlate with the density of CR-immunoreactive (IR) GABAergic neurons in the dlPFC, using the Stanley Neuropathology Consortium Integrative Database (SNCID, http://sncid.stanleyresearch.org/), which is a web-based tool used to integrate Stanley Medical Research Institute (SMRI) data sets. We found that the density of CR-IR GABAergic neurons was significantly lower in layer I of the dlPFC of MDD patients (n=15) than in that of unaffected controls (n=15) (p=0.021). CR-IR GABAergic neuronal changes were positively correlated with changes in several markers for glial cells and pyramidal neurons in the dlPFC of all SNC subjects (n=60). We also found that the glutamate changes negatively correlated with glial fibrillary acidic protein (GFAP) expression levels and CR-IR GABAergic neuronal density in the prefrontal cortex of all SNC subjects (P<0.05). These findings yield some insight into the mechanism by which increased glutamatergic neurotransmission leads to excitotoxic damage both in neurons and glial cells in the dlPFC of MDD patients.

Reliability and Validity of the Korean Version of the Childhood Trauma Questionnaire-Short Form for Psychiatric Outpatients

Objective The Childhood Trauma Questionnaire (CTQ) is perhaps the most widely used and well-studied retrospective measure of childhood abuse or neglect. This study tested the initial reliability and validity of a Korean translation of the Childhood Trauma Questionnaire (CTQ-K) among non-psychotic psychiatric outpatients. Methods The CTQ-K was administered to a total of 163 non-psychotic psychiatric outpatients at a university-affiliated training hospital. Internal consistency, four-week test-retest reliability, and validity were calculated. A portion of the participants (n=65) also completed the Trauma Assessment Questionnaire (TAQ), the Impact of Events Scale-Revised, and the Dissociative Experiences Scale-Taxon. Results Four-week test-retest reliability was high (r=0.87) and internal consistency was good (Cronbachs α=0.88). Each type of childhood trauma was significantly correlated with the corresponding subscale of the TAQ, thus confirming its concurrent validity. In addition, the CTQ-K total score was positively related to post-traumatic symptoms and pathological dissociation, demonstrating the convergent validity of the scale. The CTQ-K was also negatively correlated with the competence and safety subscale of the TAQ, confirming discriminant validity. Additionally, we confirmed the factorial validity by identifying a five-factor structure that explained 64% of the total variance. Conclusion Our study indicates that the CTQ-K is a measure of psychometric soundness that can be used to assess childhood abuse or neglect in Korean patients. It also supports the cross-cultural equivalence of the scale.

Supplementation of n-3 Polyunsaturated Fatty Acids for Major Depressive Disorder: A Randomized, Double-Blind, 12-Week, Placebo-Controlled Trial in Korea

Background: Controversy over the efficacy of n-3 polyunsaturated fatty acids (PUFAs) in depression continues to this day. The present study investigated the hypothesis that n-3 PUFA supplementation reduces depressive symptoms in Korean patients with major depressive disorder. Methods: In a randomized, double-blind, placebo-controlled, 12-week, parallel-group trial, 35 patients with Center for Epidemiological Studies Depression Scale Korean version (CES-D-K) scores ≥25 and depression confirmed by a psychiatrist were assigned to take either 3 capsules of n-3 PUFAs (1,140 mg of EPA + 600 mg of DHA; n = 18) or placebo (olive oil + safflower oil; n = 17). Results: Supplementation with n-3 PUFAs significantly reduced Clinical Global Impression Improvement (CGI-I) scores as compared with intake of placebo using intention-to-treat analysis with last-observation-carried-forward after adjusting for energy, fat, and fish intake. However, the CES-D-K, Hamilton Depression Rating Scale-17, and Clinical Global Impression Scale scores did not significantly differ between the n-3 PUFA and placebo groups. After supplementation with n-3 PUFAs, the erythrocyte levels of n-3 PUFAs were significantly increased, but n-6 PUFA levels were decreased. Conclusions: n-3 PUFAs demonstrated an advantage over placebo that did not reach clinical significance, although CGI-I score was significantly decreased in the n-3 PUFA group as compared with the placebo group.

Carbamylated erythropoietin promotes neurite outgrowth and neuronal spine formation in association with CBP/p300

Both erythropoietin (EPO) and carbamylated EPO (cEPO) have been shown to increase the length of neurites and spine density in neurons. However, the molecular mechanism underlying the EPO- and cEPO-induced neuronal differentiation has yet to be investigated. To address this issue, we investigated epigenetic modifications that regulate gene expression in neurons. Neurons treated with EPO or cEPO display an upregulation of E1A-binding protein (p300) and p300-mediated p53 acetylation, possibly increasing the transactivation activity of p53 on growth-associated protein 43 (GAP43). Treatment of cells with cEPO markedly increases spine formation and potentiates p300-mediated transactivation of PSD95, Shank2 and 3 compared to EPO. These results demonstrate that cEPO controls neuronal differentiation via acetylation of transcription factors and subsequent transactivation of target genes. These findings have important medical implications because cEPO is of interest in the development of therapeutic agents against neuropsychiatric disorders.

Fluoxetine Up-Regulates Bcl-xL Expression in Rat C6 Glioma Cells.

Objective To analyze both differentially expressed genes and the Bcl-xL protein expression after acute and chronic treatment with fluoxetine in rat C6 glioma cells. Methods C6 glioma cells were cultured for 24 h or 72 h after treatment with 10 µM fluoxetine, and gene expression patterns were observed using microarray and qRT-PCR. Then, cells were cultured for 6 h, 24 h, 72 h or 96 h after treatment with 10 µM fluoxetine, and the expression of Bcl-xL protein was measured using western blot. Results As determined by microarray, treatment with fluoxetine for 24 h up-regulated 33 genes (including Bcl-xL and NCAM140) and down-regulated 7 genes (including cyclin G-associated kinase). Treatment with fluoxetine for 72 h up-regulated 53 genes (including Gsα and Bcl-xL) and down-regulated 77 genes (including Gαi2 and annexin V). Based on the qRT-PCR results, there was an increase in Gsα mRNA and a decrease in Gαi2 mRNA at 72 h in fluoxetine-treated cells as compared to control, a result that was consistent with microarray. We also observed an increase in Bcl-xL mRNA (both at 24 h and at 72 h) in fluoxetine-treated cells as compared to control, demonstrating a tendency to increase gradually. Bcl-xL protein expression increased as the duration of fluoxetine treatment increased. Conclusion These results suggest that chronic treatment with fluoxetine not only initiates the cAMP pathway through inducing Gsα expression but also induces Bcl-xL expression, thus inhibiting apoptosis.

Detection of concealed information: combining a virtual mock crime with a P300-based Guilty Knowledge Test.

The present study examined the detection of concealed information by combining a virtual mock crime with a P300-based Guilty Knowledge Test (GKT). Thirty-eight male participants were assigned to one of two groups: a guilty group that committed a mock crime to conceal a lost roll of bills in a computer simulation of a virtual library and an innocent group that was free from concealed information. Remarkably, the guilty group reacted with stronger P300 peak amplitudes to crime-relevant than to irrelevant stimuli, whereas the innocent group had similar P300 responses between crime-relevant and irrelevant stimuli. Deception-related cognitive activity based on P300 was revealed as a valid marker to differentiate between guilty and innocent. This is a highly empirical study combining a virtual mock crime with a P300-based GKT to detect deception. These results may be applied to a variety of areas dealing with not only forensic investigation but also health and medical research concerning deception as a symptom.

Comparison of Neurite Outgrowth Induced by Erythropoietin (EPO) and Carbamylated Erythropoietin (CEPO) in Hippocampal Neural Progenitor Cells.

A previous animal study has shown the effects of erythropoietin (EPO) and its non-erythropoietic carbamylated derivative (CEPO) on neurogenesis in the dentate gyrus. In the present study, we sought to investigate the effect of EPO on adult hippocampal neurogenesis, and to compare the ability of EPO and CEPO promoting dendrite elongation in cultured hippocampal neural progenitor cells. Two-month-old male BALB/c mice were given daily injections of EPO (5 U/g) for seven days and were sacrificed 12 hours after the final injection. Proliferation assays demonstrated that EPO treatment increased the density of bromodeoxyuridine (BrdU)-labeled cells in the subgranular zone (SGZ) compared to that in vehicle-treated controls. Functional differentiation studies using dissociated hippocampal cultures revealed that EPO treatment also increased the number of double-labeled BrdU/microtubule-associated protein 2 (MAP2) neurons compared to those in vehicle-treated controls. Both EPO and CEPO treatment significantly increased the length of neurites and spine density in MAP2(+) cells. In summary, these results provide evidences that EPO and CEPO promote adult hippocampal neurogenesis and neuronal differentiation. These suggest that EPO and CEPO could be a good candidate for treating neuropsychiatric disorders such as depression and anxiety associated with neuronal atrophy and reduced hippocampal neurogenesis.

Changes in vascular endothelial growth factor (VEGF) induced by the Morris water maze task.

The present study was undertaken to evaluate the effects on hippocampal vascular endothelial growth factor (VEGF) levels in rats when they experience hippocampal-dependent spatial learning via the Morris water maze (MWM) task. Rats underwent one of two different versions of the MWM: weak or intensive. After one day of intensive training, a highly sensitive enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF protein levels in the hippocampus, cortex, and serum, and higher levels were found in the trained group compared to a naive control group. VEGF levels also increased in rats that swam only for durations equal to the intensive training periods. In contrast, rats trained under the weaker MWM paradigm for five days showed a decrease in hippocampal VEGF protein level. Mimicking increases in neuronal VEGF in the hippocampus by direct infusion of VEGF into CA1 resulted in up-regulation of the phosphorylation of the cAMP response element-binding (CREB) protein and the Ca2+/calmodulin-dependent protein kinases II (CaMKII). These results suggest that VEGF may be a physiological parameter involved in learning procedures that include physical activity.

Fluoxetine Increases the Expression of NCAM140 and pCREB in Rat C6 Glioma Cells

Objective Dysfunction of neural plasticity in the brain is known to alter neural networks, resulting in depression. To understand how fluoxetine regulates molecules involved in neural plasticity, the expression levels of NCAM, NCAM140, CREB and pCREB, in rat C6 glioma cells after fluoxetine treatment were examined. Methods C6 cells were cultured after 20 min or after 6, 24 or 72 h treatments with 10 µM fluoxetine. Immunocytochemistry was used to determine the effect of fluoxetine on the expression of NCAM. Western blot analysis was used to measure the expression levels of NCAM140 and CREB and the induction of pCREB after fluoxetine treatment. Results NCAM expression following 72-h fluoxetine treatment was significantly increased around cell membranes compared to control cells. Cells treated with fluoxetine for 6 and 72 h showed a significant increase in NCAM140 expression compared to cells treated for 20 min. The level of pCREB in the cells treated with fluoxetine for 72 h not only increased more than 60%, but was also significantly different when compared with the other treatment times. The 72-h fluoxetine treatment led to the increase of NCAM140 and the phosphorylation of CREB in C6 cells. Conclusion Our findings indicate that fluoxetine treatment regulates neuronal plasticity and neurite outgrowth by phosphorylating and activating CREB via the NCAM140 homophilic interaction-induced activation of the Ras-MAPK pathway.

Predicting Autism Spectrum Disorder Using Blood-based Gene Expression Signatures and Machine Learning

Objective The aim of this study was to identify a transcriptomic signature that could be used to classify subjects with autism spectrum disorder (ASD) compared to controls on the basis of blood gene expression profiles. The gene expression profiles could ultimately be used as diagnostic biomarkers for ASD. Methods We used the published microarray data (GSE26415) from the Gene Expression Omnibus database, which included 21 young adults with ASD and 21 age- and sex-matched unaffected controls. Nineteen differentially expressed probes were identified from a training dataset (n=26, 13 ASD cases and 13 controls) using the limma package in R language (adjusted p value <0.05) and were further analyzed in a test dataset (n=16, 8 ASD cases and 8 controls) using machine learning algorithms. Results Hierarchical cluster analysis showed that subjects with ASD were relatively well-discriminated from controls. Based on the support vector machine and K-nearest neighbors analysis, validation of 19-DE probes with a test dataset resulted in an overall class prediction accuracy of 93.8% as well as a sensitivity and specificity of 100% and 87.5%, respectively. Conclusion The results of our exploratory study suggest that the gene expression profiles identified from the peripheral blood samples of young adults with ASD can be used to identify a biological signature for ASD. Further study using a larger cohort and more homogeneous datasets is required to improve the diagnostic accuracy.