Multimodal neuroimaging network associated with executive function in adolescent major depressive disorder patients via cognition-guided magnetic resonance imaging fusion.

Adolescents are high-risk population for major depressive disorder. Executive dysfunction emerges as a common feature of depression and exerts a significant influence on the social functionality of adolescents. This study aimed to identify the multimodal co-varying brain network related to executive function in adolescent with major depressive disorder. A total of 24 adolescent major depressive disorder patients and 43 healthy controls were included and completed the Intra-Extra Dimensional Set Shift Task. Multimodal neuroimaging data, including the amplitude of low-frequency fluctuations from resting-state functional magnetic resonance imaging and gray matter volume from structural magnetic resonance imaging, were combined with executive function using a supervised fusion method named multimodal canonical correlation analysis with reference plus joint independent component analysis. The major depressive disorder showed more total errors than the healthy controls in the Intra-Extra Dimensional Set Shift task. Their performance on the Intra-Extra Dimensional Set Shift Task was negatively related to the 14-item Hamilton Rating Scale for Anxiety score. We discovered an executive function-related multimodal fronto-occipito-temporal network with lower amplitude of low-frequency fluctuation and gray matter volume loadings in major depressive disorder. The gray matter component of the identified network was negatively related to errors made in Intra-Extra Dimensional Set Shift while positively related to stages completed. These findings may help to deepen our understanding of the pathophysiological mechanisms of cognitive dysfunction in adolescent depression.

Differential effects of sleep deprivation on behavior and microglia in a brain-region-specific manner in young and aged male mice.

Microglia, resident immune cells in the central nervous system, constantly monitor the state of the surrounding brain activity. The animal model induced by sleep deprivation (SD) is widely used to study the pathophysiological mechanisms of insomnia and bipolar disorder. However, it remains unclear whether SD affects behaviors in young and aged male mice and microglia in various brain regions. In this study, we confirmed brain region-specific changes in microglial density and morphology in the accumbens nucleus (Acb), amygdala (AMY), cerebellum (Cb), corpus callosum (cc), caudate putamen, hippocampus (HIP), hypothalamus (HYP), medial prefrontal cortex (mPFC), and thalamus (TH) of young mice. In addition, the density of microglia in old mice was higher than that in young mice. Compared with young mice, old mice showed a markedly increased microglial size, decreased total length of microglial processes, and decreased maximum length. Importantly, we found that 48-h SD decreased microglial density and morphology in old mice, whereas SD increased microglial density and morphology in most observed brain regions in young mice. SD-induced hyperactivity was observed only in young mice but not in old mice. Moreover, microglial density (HIP, AMY, mPFC, CPu) was significantly positively correlated with behaviors in SD- and vehicle-treated young mice. Contrarily, negative correlations were shown between the microglial density (cc, Cb, TH, HYP, Acb, AMY) and behaviors in vehicle-treated young and old mice. These results suggest that SD dysregulates the homeostatic state of microglia in a region- and age-dependent manner. Microglia may be involved in regulating age-related behavioral responses to SD.

Association of the plasma complement system with brain volume deficits in bipolar and major depressive disorders.

BACKGROUND: Inflammation plays a crucial role in the pathogenesis of major depressive disorder (MDD) and bipolar disorder (BD). This study aimed to examine whether the dysregulation of complement components contributes to brain structural defects in patients with mood disorders. METHODS: A total of 52 BD patients, 35 MDD patients, and 53 controls were recruited. The human complement immunology assay was used to measure the levels of complement factors. Whole brain-based analysis was performed to investigate differences in gray matter volume (GMV) and cortical thickness (CT) among the BD, MDD, and control groups, and relationships were explored between neuroanatomical differences and levels of complement components. RESULTS: GMV in the medial orbital frontal cortex (mOFC) and middle cingulum was lower in both patient groups than in controls, while the CT of the left precentral gyrus and left superior frontal gyrus were affected differently in the two disorders. Concentrations of C1q, C4, factor B, factor H, and properdin were higher in both patient groups than in controls, while concentrations of C3, C4 and factor H were significantly higher in BD than in MDD. Concentrations of C1q, factor H, and properdin showed a significant negative correlation with GMV in the mOFC at the voxel-wise level. CONCLUSIONS: BD and MDD are associated with shared and different alterations in levels of complement factors and structural impairment in the brain. Structural defects in mOFC may be associated with elevated levels of certain complement factors, providing insight into the shared neuro-inflammatory pathogenesis of mood disorders.

[Correlation between altered levels of neurotransmitters in the frontal lobe and hippocampus and behavioral abnormalities in a Clockdelta19 mutant mice modeling bipolar manic disorder].

OBJECTIVE: To explore the correlation between altered levels of neurotransmitters in the frontal lobe and hippocampus and behavioral abnormalities in a Clockdelta19 variant mice modeling bipolar disorder manic disorder. METHODS: Open field test and Elevated plus-maze test were carried out on the Clockdelta19 mutant and wild-type control groups. The frontal lobe and hippocampus of Clockdelta19 mutant mice and controls were dissected, and neurotransmitters in tissue extracts were analyzed by high-performance liquid chromatography and mass spectrometry. The concentration of neurotransmitters and behavioral indicators were assessed by t test and Pearson correlation analysis using SPSS 22.0. RESULTS: The Clockdelta19 mutant mice showed a significant increase in activity, albeit with no difference in the level of anxiety from the wild-type controls, which suggested that the Clockdelta19 mutant mice can be used as a model for manic attack of bipolar disorder. Altered neurotransmitter levels were detected in the frontal and hippocampal regions, including elevated histamine in the left hippocampus, reduced histamine in the right hippocampus, reduced gamma-aminobutyric acid (GABA) in bilateral hippocampus, elevated dihydroxyphenylalanine (DOPA) in the left frontal lobe and reduced DOPA in the right hippocampus, and decreased glutamine in bilateral frontal lobes. The reduced glutamine in the left frontal lobe and GABA in the right hippocampus correlated with the increased activity of Clockdelta19 mutant mice. CONCLUSION: Clockdelta19 mutant mice showed abnormal behavior with increased activity. Reduced glutamine in the left frontal lobe and GABA in the right hippocampus were correlated with increased activity.

Plasma neuropeptides as circulating biomarkers of multifactorial schizophrenia.

BACKGROUND: Promising biomarkers would be used to improve the determination of diagnosis and severity, as well as the prediction of symptomatic and functional outcomes of schizophrenia. BASIC PROCEDURES: In this study, we used three different mouse models induced by a genetic factor (PV-Cre; ErbB4-/-, G group), an environmental stressor (adolescent social isolation, G group), and a combination of genetic factor and environmental stressor (PV-Cre; ErbB4-/- mice with isolation, G × E group). Attenuated PPI (%) confirmed the successful establishment of three schizophrenia-like mouse models. To evaluate whether neuropeptide levels in plasma would be potential biomarkers of different schizophrenia models in our work, we used MILLIPLEX® MAP method to simultaneously measure 6 critical neuropeptides in plasma. MAIN FINDINGS: Among the evaluated neuropeptides, increased neurotensin tends to be associated with genetic factors of schizophrenia, increased orexin A seems to be a biomarker of an interplay between genetic and social isolation, while higher plasma oxytocin might be more apt to be responsive to social isolation. The potential biomarkers are mostly independent of sex. CONCLUSIONS: This research would provide novel clues to develop circulating biomarkers of plasma neuropeptides for multifactorial schizophrenia.

[Pathway-focused correlation study of genome-wide methylation status with visual memory].

OBJECTIVE To explore the biological processes and pathways associated with memory function which may be regulated by gene promoter methylation. METHODS The genome-wide promoter methylation statuses in 9 healthy individuals were analyzed with a Multiplex HG18 CpG Promoter chip. Genes with promoter methylation statuses strongly correlated with both immediate and delayed visual memory function were preceded for pathway and physical interactions analysis. RESULTS Sixty nine genes have been correlated with both immediate and delayed visual memory functions. Twenty two pathways, with a Q-value of < 0.05, were identified by the pathway and physical interactions analysis, which included energy metabolism, axon guidance, tyrosine kinase activity, anterograde synaptic vesicle transport, and leukocyte migration and differentiation. CONCLUSION Pathways related with memory function may be regulated by DNA methylation.

[Effect of Risperidone on BDNF-TrkB Signaling Pathway in Rat Brain].

OBJECTIVE: To investigate the effect of risperidone on the expression of brain-derived neurotrophic factor (BDNF) and its receptors, tyrosine kinase receptor (TrkB) and P75 neurotrophin receptor (P75NTR) in rat brain. METHODS: Sixteen SD rats were divided into two groups (n = 8 for each group). The rats in experimental group were treated with risperidone [0.25 mg/(kg · d)] for 14 d, while the control group was given placebo. Total RNA sample in prefrontal cortex, temporal cortex and hippocampus was extracted, and the expression of BDNF, TrkB and P75NTR mRNA were determined by quantitative real-time PCR. RESULTS: The treatment of risperidone significantly up-regulated the expressions of BDNF and TrkB in prefrontal cortex, temporal cortex and hippocampus, while the expression of P75NTR was not significantly changed. CONCLUSION: Risperidone upregulated BDNF-TrkB signaling, but not BDNF-P75NTR signaling, which may be helpful for the further pharmacological study of risperidone.

[Regulation of PI3K-Akt-GSK3ß signaling pathway in U251 cells by risperidone].

OBJECTIVE: To investigate the effect of risperidone, an antipsychotic drug, on the Akt-GSK3ß pathway and the role of PI3K in dopamine D2 receptor (DRD2) expression and Akt-GSK3ß signal pathway. METHODS: Human glioma cells (U251) were cultured in vitro. Cells without any treatment as control, Western blotting was used for measuring the expression of Akt (Thr308 and Ser473) and GSK3ß (Ser9) protein phosphorylation by risperidone and LY294002 in U251 cell, and real-time PCR was used for detecting the expression of DRD2 mRNA. RESULTS: Risperidone has significantly enhanced the expression of phosphorylated Akt and phosphorylated GSK3ß (P< 0.05), but did not alter the mRNA expression of DRD2. LY294002 could reduce the phosphorylation of Akt and GSK3ß (P< 0.01, P< 0.05), and also decrease the DRD2 mRNA (P<0 .05). CONCLUSION: Risperidone can activate the Akt-GSK3ß signaling pathway in the U251 cells, and PI3K is a common regulatory site in Akt-GSK3ß signaling and D2 receptor gene expression.

Changes of structural functional connectivity coupling and its correlations with cognitive function in patients with major depressive disorder.

BACKGROUND: Previous neuroimaging studies have reported structural and functional brain abnormalities in major depressive disorder (MDD). This study aimed to explore whether the coherence of structural-functional networks was affected by disease and investigate its correlation with clinical manifestations. METHODS: The severity of symptoms and cognitive function of 121 MDD patients and 139 healthy controls (HC) were assessed, and imaging data, including diffusion tensor imaging, T1 structural magnetic resonance imaging (MRI) and resting-state functional MRI, were collected. Spearman correlation coefficients of Kullback-Leibler similarity (KLS), fiber number (FN), fractional anisotropy (FA) and functional connectivity (FC) were calculated as coupling coefficients. Double-weight median correlation analysis was conducted to investigate the correlations between differences in brain networks and clinical assessments. RESULTS: The percentage of total correct response of delayed matching to sample and the percentage of delayed correct response of pattern recognition memory was lower in MDD. Compared with the HC, KLS-FC coupling between the parietal lobe and subcortical area, FA-FC coupling between the temporal and parietal lobe, and FN-FC coupling in the frontal lobe was lower in MDD. Several correlations between structural-functional connectivity and clinical manifestations were identified. LIMITATIONS: First, our study lacks longitudinal follow-up data. Second, the sample size was relatively small. Moreover, we only used the Anatomical Automatic Labeling template to construct the brain network. Finally, the validation of the causal relationship of neuroimaging-behavior factors was still insufficient. CONCLUSIONS: The alternation in structural-functional coupling were related to clinical characterization and might be involved in the neuropathology of depression.

Dysconnectivity of the brain functional network and abnormally expressed peripheral transcriptional profiles in patients with anxious depression.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous mental disorder, and accompanying anxiety symptoms, known as anxious depression (AD), are the most common subtype. However, the pathophysiology of AD may be distinct in depressed patients without anxiety (NAD) and remains unknown. This study aimed to investigate the relationship between functional connectivity and peripheral transcriptional profiles in patients with AD and NAD. METHODS: Functional imaging data were collected to identify differences in functional networks among patients with AD (n = 66), patients with NAD (n = 115), and healthy controls (HC, n = 200). The peripheral transcriptional data were clustered as co-expression modules, and their associations with AD, AND, and HC were analyzed. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of the genes in the significant module were performed. Correlation analysis was performed to identify functional network-associated gene co-expression modules. RESULTS: A network was identified which consisted of 23 nodes and 28 edges that were significantly different among three sample groups. The regions of the network were located in temporal and occipital lobe. Two gene co-expression modules were shown to be associated with NAD, and one of which was correlated with the disrupted network in the AD group. The biological function of this module was enriched in immune regulation pathways. CONCLUSION: The results suggested that immune-related mechanisms were associated with functional networks in AD.

Abnormal functional connectivity within the prefrontal cortex is associated with multiple plasma lipid species in major depressive disorder.

BACKGROUND: Abnormalities in functional connectivity (FC) in major depressive disorder (MDD) have been widely reported. Analysis of the relationship between FC and plasma lipid profiles would be meaningful in the exploration of pathophysiological mechanisms and helpful for the identification of biomarkers for MDD. METHODS: Patients with MDD (n = 49) and healthy controls (HC, n = 87) were recruited. Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected for FC construction. The plasma lipid profiles were acquired using ultra-performance liquid chromatography (UPLC) and mass spectrometry (MS) analysis and clustered as co-expression modules. The differential FC and lipid modules between HCs and patients with MDD were identified, and then the association between FC and lipid co-expression modules was analyzed using correlation analysis. The modules associated molecular function was explored using metabolite set enrichment analysis (MSEA). RESULTS: MDD-associated FC and lipid co-expression modules were identified. One module was associated with FC values between the right orbital part of the middle frontal gyrus and the opercular part of the left inferior frontal gyrus, which was enriched in lipid sets of diacylglycerols and fatty alcohols; another module was associated with FC values between the right middle frontal gyrus and the right anterior cingulate and paracingulate gyri, which was enriched in lipid sets of glycerophosphocholines and glycerophosphoethanolamines. CONCLUSION: Our results indicated that abnormal FC in the prefrontal cortex is associated with multiple plasma lipid species, which may provide novel clues for exploring the pathophysiology of MDD.

The impact of childhood trauma on emotional distress and the moderating role of sense of coherence among college students in China.

Childhood trauma is strongly linked to emotional distress. However, few studies have explored the impact of sense of coherence (SOC) on the relationship between childhood trauma and emotional distress in college students. This study aimed to explore its impact on the relationship between childhood trauma and emotional distress. Analyzing data from 2307 Chinese college students, we found that SOC moderated the association between childhood trauma and anxiety/depression levels. Females showed higher SOC and lower anxiety/depression despite experiencing more childhood trauma. Multiple linear regression revealed that anxiety was negatively associated with SOC(P < 0.001) and grade(P = 0.027), and positively with childhood trauma(P < 0.001) and male gender(P = 0.004). Similarly, the depression exhibited similar associations. SOC moderated negatively the relationship between CTQ and anxiety, as well as between CTQ and depression. Childhood trauma is associated with increased emotional distress risk among college students, but a strong SOC can reduce this risk.

Identification and characterization of poly(I:C)-induced molecular responses attenuated by nicotine in mouse macrophages.

To further our understanding of the effects of nicotine on the molecular responses of macrophages during virus or virus-like infections, poly(I:C)-stimulated macrophage-like RAW264.2 cells or mouse primary peritoneal macrophages were challenged with nicotine; and their molecular responses were evaluated using a qRT-PCR array, antibody array, ELISA, Western blotting, and Ca(2+) imaging. Of 51 genes expressed in the Toll-like receptor (TLR) and RIG-I-like receptor (RLR) pathways, mRNA expression of 15 genes in RAW264.7 cells was attenuated by nicotine, of which mRNA expression of IL-6, TNF-α, and IL-1ß was confirmed to be attenuated in peritoneal macrophages. Concurrently, nicotine treatment attenuated the release of IL-6 and TNF-α from poly(I:C)-stimulated macrophages. However, when poly(I:C)-stimulated macrophages were challenged with nicotine plus α-bungarotoxin (α-BTX), secretion of IL-6 and TNF-α was found to be in a level seen with poly(I:C) stimulation only, indicating that α7-nAChR, a highly Ca(2+) permeable ion channel sensitive to blockade by α-BTX, is involved in this process. Furthermore, results from an antibody array indicated that nicotine treatment attenuated the phosphorylation of 82 sites, including Thr286 on CaMKIIα, from poly(I:C)-stimulated RAW264.7 cells, of which 28 are expressed in the downstream cascade of Ca(2+) signaling. Coincidentally, poly(I:C)-stimulated macrophages showed attenuated expression of phosphorylated CaMKIIα when pretreated with nicotine. In addition, nicotine attenuated intracellular Ca(2+) signal from poly(I:C)-stimulated RAW264.7 cells. Collectively, these results indicate that poly(I:C)-induced molecular responses of macrophages could be significantly attenuated by nicotine.

[Genome-wide linkage scan for an ethnic Han Chinese pedigree affected with schizophrenia].

OBJECTIVE: To perform genome-wide linkage analysis for an ethnic Han Chinese pedigree with schizophrenia in order to locate the susceptibility genes. METHODS: Genomic DNA was extracted from 4 mL of peripheral blood using conventional phenol-chloroform method. Illumina Infinium Linkage 24 BeadChips chip was used for determining the genotypes through detection of single nucleotide polymorphisms (SNPs). After processing the raw data using Illumina BeadStudio software, two-point nonparametric linkage analysis and two-point parametric linkage analysis were performed with Merlin software. RESULTS: By two-point nonparametric linkage analysis, 27 sites with high LOD scores (LOD=0.63-0.75, P U+003C 0.05) were identified. Among these, 3 SNPs(rs993694, rs992690 rs1861577) were located in 12p12.3 region, whilst the remainders were located in 4p12-q22 region. Two-point parametric linkage analysis under a dominant model has yielded almost identical results. CONCLUSION: Chromosomal regions 4p12-q22 and 12p12.3 probably contain susceptibility genes for schizophrenia.

DNA Tetrahedra-Based Delivery of MicroRNA-22 to Reduce Depressive Symptoms in Mice.

Major depressive disorder (MDD) is a common illness with an increasing lifetime prevalence. Thus, an increasing number of studies have investigated the association between MDD and microRNAs (miRNAs), which are a novel approach for treating depression. However, the therapeutic potential of miRNA-based strategies has several limitations. To overcome these limitations, DNA tetrahedra (TDNs) have been used as piggyback materials. In this study, we successfully used TDNs as carriers of miRNA-22-3p (miR-22-3p) and synthesized a novel DNA nanocomplex (TDN-miR-22-3p), which was used in a lipopolysaccharide (LPS)-induced depression cell model. The results suggest that miR-22-3p may regulate inflammation by regulating phosphatase and tensin homologue (PTEN), an important regulatory molecule in the PI3K/AKT pathway, and downregulating the expression of NLRP3. We further validated the role of TDN-miR-22-3p in vivo using an LPS-induced animal model of depression. The results indicate that it ameliorated depression-like behavior and attenuated the expression of inflammation-related factors in mice. This study demonstrates the establishment of a straightforward and efficacious miRNA delivery system and the potential of TDNs as therapeutic vectors and tools for mechanistic studies. To the best of our knowledge, this is the first study to use TDNs in combination with miRNAs to treat depression.

Down-regulated miR-16-2 in peripheral blood is positively correlated with decreased bilateral insula volume in patients with major depressive disorder.

BACKGROUND: The downregulated microRNA-16-2-3p (miR-16-2) had been believed to be associated with major depressive disorder (MDD). This study aimed to investigate the potential of miR-16-2 as a biomarker for MDD by analysing its expression levels, furthermore, to explore the relationship between miR-16-2, clinical symptoms and alterations in grey matter volume (GMV) in MDD patients. METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression level of miR-16-2 in 48 drug-naïve patients with MDD and 50 healthy controls (HCs). We conducted ROC curve analysis to assess the diagnostic value of miR-16-2 in MDD, and evaluated its ability to predict antidepressant response by reassessing depressive and anxiety symptoms after treatment. Voxel-based morphometry was carried out to explore alterations in regional GMV that may be associated with MDD. Pearson analysis was used to explore the relationship between miR-16-2 expression, clinical symptoms, and altered GMV in the brains of MDD patients. RESULTS: We found that MDD patients had significantly downregulated miR-16-2 expression, which was negatively correlated with HAMD-17 and HAMA-14 scores, and had great diagnostic value for MDD (AUC = 0.806, 95 % CI: 0.721-0.891). In addition, MDD patients had significantly lower GMV in the bilateral insula and left superior temporal gyrus (STG_L) than HCs. GMV reduction in the bilateral insula was found to be correlated with miR-16-2 expression. CONCLUSIONS: Our findings support the potential value of miRNA-16-2 as a biomarker for MDD. It also suggests that miRNA-16-2 may be associated with abnormal insula and involved in pathophysiological mechanisms of MDD.

Decreased plasma neuropeptides in first-episode schizophrenia, bipolar disorder, major depressive disorder: associations with clinical symptoms and cognitive function.

Background: There is an urgent need to identify differentiating and disease-monitoring biomarkers of schizophrenia, bipolar disorders (BD), and major depressive disorders (MDD) to improve treatment and management. Methods: We recruited 54 first-episode schizophrenia (FES) patients, 52 BD patients, 35 MDD patients, and 54 healthy controls from inpatient and outpatient clinics. α-Melanocyte Stimulating Hormone (α-MSH), ß-endorphin, neurotensin, orexin-A, oxytocin, and substance P were investigated using quantitative multiplex assay method. Psychotic symptoms were measured using the Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale (PANSS), manic symptoms using the Young Mania Rating Scale (YMRS), and depressive symptoms using 17 item-Hamilton Depression Rating Scale (HAMD). We additionally measured cognitive function by using a battery of tests given to all participants. Results: α-MSH, neurotensin, orexin-A, oxytocin, and substance P were decreased in the three patient groups compared with controls. Neurotensin outperformed all biomarkers in differentiating patient groups from controls. There were no significant differences for 6 neuropeptides in their ability to differentiate between the three patient groups. Higher neurotensin was associated with better executive function across the entire sample. Lower oxytocin and higher substance p were associated with more psychotic symptoms in FES and BD groups. ß-endorphin was associated with early morning wakening symptom in all three patient groups. Conclusion: Our research shows decreased circulating neuropeptides have the potential to differentiate severe mental illnesses from controls. These neuropeptides are promising treatment targets for improving clinical symptoms and cognitive function in FES, BD, and MDD.

Depletion of microglia with PLX3397 attenuates MK-801-induced hyperactivity associated with regulating inflammation-related genes in the brain.

Acute administration of MK-801 (dizocilpine), an N-methyl-D-aspartate receptor (NMDAR) antagonist, can establish animal models of psychiatric disorders. However, the roles of microglia and inflammation-related genes in these animal models of psychiatric disorders remain unknown. Here, we found rapid elimination of microglia in the prefrontal cortex (PFC) and hippocampus (HPC) of mice following administration of the dual colony-stimulating factor 1 receptor (CSF1R)/c-Kit kinase inhibitor PLX3397 (pexidartinib) in drinking water. Single administration of MK-801 induced hyperactivity in the open-field test (OFT). Importantly, PLX3397-induced depletion of microglia prevented the hyperactivity and schizophrenia-like behaviors induced by MK-801. However, neither repopulation of microglia nor inhibition of microglial activation by minocycline affected MK-801-induced hyperactivity. Importantly, microglial density in the PFC and HPC was significantly correlated with behavioral changes. In addition, common and distinct glutamate-, GABA-, and inflammation-related gene (116 genes) expression patterns were observed in the brains of PLX3397- and/or MK-801-treated mice. Moreover, 10 common inflammation-related genes ( CD68, CD163, CD206, TMEM119, CSF3R, CX3CR1, TREM2, CD11b, CSF1R, and F4/80) with very strong correlations were identified in the brain using hierarchical clustering analysis. Further correlation analysis demonstrated that the behavioral changes in the OFT were most significantly associated with the expression of inflammation-related genes ( NLRP3, CD163, CD206, F4/80, TMEM119, and TMEM176a), but not glutamate- or GABA-related genes in PLX3397- and MK-801-treated mice. Thus, our results suggest that microglial depletion via a CSF1R/c-Kit kinase inhibitor can ameliorate the hyperactivity induced by an NMDAR antagonist, which is associated with modulation of immune-related genes in the brain.

Association of elevated levels of peripheral complement components with cortical thinning and impaired logical memory in drug-naïve patients with first-episode schizophrenia.

Schizophrenia has been linked to polymorphism in genes encoding components of the complement system, and hyperactive complement activity has been linked to immune dysfunction in schizophrenia patients. Whether and how specific complement components influence brain structure and cognition in the disease is unclear. Here we compared 52 drug-naïve patients with first-episode schizophrenia and 52 healthy controls in terms of levels of peripheral complement factors, cortical thickness (CT), logical memory and psychotic symptoms. We also explored the relationship between complement factors with CT, cognition and psychotic symptoms. Patients showed significantly higher levels of C1q, C4, factor B, factor H, and properdin in plasma. Among patients, higher levels of C3 in plasma were associated with worse memory recall, while higher levels of C4, factor B and factor H were associated with thinner sensory cortex. These findings link dysregulation of specific complement components to abnormal brain structure and cognition in schizophrenia.

YBX1-Mediated DNA Methylation-Dependent SHANK3 Expression in PBMCs and Developing Cortical Interneurons in Schizophrenia.

Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases. The methylated DNA immunoprecipitation-chip (MeDIP-chip) is performed to investigate genome-wide DNA methylation dysregulation in peripheral blood mononuclear cells (PBMCs) of patients with first-episode SCZ (FES). Results show that the SHANK3 promoter is hypermethylated, and this hypermethylation (HyperM) is negatively correlated with the cortical surface area in the left inferior temporal cortex and positively correlated with the negative symptom subscores in FES. The transcription factor YBX1 is further found to bind to the HyperM region of SHANK3 promoter in induced pluripotent stem cells (iPSCs)-derived cortical interneurons (cINs) but not glutamatergic neurons. Furthermore, a direct and positive regulatory effect of YBX1 on the expression of SHANK3 is confirmed in cINs using shRNAs. In summary, the dysregulated SHANK3 expression in cINs suggests the potential role of DNA methylation in the neuropathological mechanism underlying SCZ. The results also suggest that HyperM of SHANK3 in PBMCs can serve as a potential peripheral biomarker of SCZ.