| 1 | Brain Behav. Immun. 2015 May 46: 60-9 |
|---|---|
| PMID | 25728234 |
| Title | Gadd45b is an epigenetic regulator of juvenile social behavior and alters local pro-inflammatory cytokine production in the rodent amygdala. |
| Abstract | Precise regulation of the epigenome during perinatal development is critical to the formation of species-typical behavior later in life. Recent data suggests that GADD45B facilitates active DNA demethylation by recruiting proteins involved in base excision repair (BER), which will catalyze substitution of 5-methyl-cytosine (5mC) for an unmodified cytosine. While a role for GADD45B has been implicated in both hippocampal and amygdalar learning tasks, to the best of our knowledge, no study has been done investigating the involvement of GADD45B in neurodevelopmental programming of social behavior. To address this, we used a targeted siRNA delivery approach to transiently knock down GADD45B expression in the neonatal rat amygdala. We chose to examine social behavior in the juvenile period, as social deficits associated with neurodevelopmental disorders tend to emerge in humans at an equivalent age. We find that neonatal GADD45B knock-down results in altered juvenile social behavior and reduced expression of several genes implicated in psychiatric disorders, including methyl-CpG-binding protein 2 (MeCP2), Reelin, and brain derived neurotrophic factor (BDNF). We furthermore report a novel role for GADD45B in the programmed expression of ?2-adrenoceptor (Adra2a). Consistent with GADD45B's role in the periphery, we also observed changes in the expression of pro-inflammatory cytokines interleukin-6 (Il-6) and interleukin-1beta (Il-1beta) in the amygdala, which could potentially mediate or exacerbate effects of GADD45B knockdown on the organization of social behavior. These data suggest a prominent role for GADD45B in the epigenetic programming of complex juvenile social interactions, and may provide insight into the etiology of juvenile behavioral disorders such as ADHD, autism, and/or schizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | Epigenomics 2015 -1 7: 567-79 |
| PMID | 26111030 |
| Title | Gadd45b and N-methyl-D-aspartate induced DNA demethylation in postmitotic neurons. |
| Abstract | In nondividing neurons examine the role of GADD45B in active 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) removal at a gene promoter highly implicated in mental illnesses and cognition, Bdnf. Mouse primary cortical neuronal cultures with and without GADD45B siRNA transfection were treated with N-methyl-d-aspartate (NMDA). Expression changes of genes reportedly involved in DNA demethylation, Bdnf mRNA and protein and 5MC and 5HMC at Bdnf promoters were measured. GADD45B siRNA transfection in neurons abolishes the NMDA-induced increase in Bdnf IXa mRNA and reductions in 5MC and 5HMC at the Bdnf IXa promoter. These results contribute to our understanding of DNA demethylation mechanisms in neurons, and its role in regulating NMDA responsive genes implicated in mental illnesses. |
| SCZ Keywords | schizophrenia |
| 3 | J Biomed Mater Res A 2015 Feb 103: 746-61 |
| PMID | 24866321 |
| Title | Gene expression analysis of laminin-1-induced neurite outgrowth in human mesenchymal stem cells derived from bone marrow. |
| Abstract | The mechanisms underlying the differentiation of Mesenchymal stem cells (MSCs) toward neuronal cell type are not clearly understood. Earlier, we reported that laminin-1 induces neurite outgrowth in human MSCs via c-Jun/AP-1 activation through ERK, JNK, and Akt pathways. In this study, we demonstrate that laminin-1 increases the expression of proneural gene, neuroD1 and induces the expression of immediate-early biomarkers of neuronal cell-programming-Egr1, Egr3, PC3, and PC4. Gene expression profiling of MSCs cultured on laminin-1 and Poly-l-lysine for 12 h revealed differential regulation of 267 genes (>1.5 fold, p < 0.05), predominantly in the category of nervous system development and affected the pathways involved in TGF-?/TNF-? signaling, regulation of MAPK and JNK cascade. Data for 11 selected genes related to nervous system development was validated by real time PCR. Transcriptional regulatory network analysis revealed c-Jun as the key transcription factor regulating majority of differentially expressed genes and identified Disrupted in schizophrenia 1, as a novel target of c-Jun. Modeling and analysis of biological network showed selective induction of Growth Arrest and DNA damage 45 (GADD45B) and repression of NF-?B inhibitor A (NF?BIA). Collectively, our findings provide the basis for understanding the molecular mechanisms associated with laminin-1-induced neurogenic expression in MSCs. |
| SCZ Keywords | schizophrenia |
| 4 | J ECT 2015 Dec 31: 234-7 |
| PMID | 25807342 |
| Title | Microarray Analysis of Human Blood During Electroconvulsive Therapy. |
| Abstract | Electroconvulsive therapy (ECT) is currently regarded as a significant treatment option for intractable psychiatric disorders, such as catatonic schizophrenia or treatment-resistant depression; however, the underlying molecular mechanism for its therapeutic effect remains obscure. Employing microarray analysis (Human Genome U133 Plus 2.0 Array; Affymetrix, United States) of cDNA derived from the peripheral blood of patients with catatonic schizophrenia (n = 5), we detected a significant change in 145 genes (0.68%) before and after modified ECT (mECT). Moreover, we performed quantitative polymerase chain reaction validation of genes that had previously been suggested to be functionally related to schizophrenia. Of 4 genes examined (AKT3, TCF7, PPP3R1, and GADD45B), only TCF7 was increased during the mECT procedure (P = 0.0025). This study describes the first attempt to uncover the molecular mechanism of mECT using a microarray assay of mRNA derived from peripheral blood, and our results suggest that the TCF family may play a role in the functional mechanism of mECT. |
| SCZ Keywords | schizophrenia |