p75NTR enhances cognitive dysfunction in a mouse Alzheimer's disease model by inhibiting microRNA-210-3p-mediated PCYT2 through activation of NF-κB.

Alzheimer's disease (AD) is a main cause of dementia and exhibits abnormality in cognitive behaviors. Here, we probed into the role of p75 neurotrophin receptor (p75NTR) in cognitive dysfunction in AD. Primarily, C57BL/6 mouse and neuroblastoma cells were treated by amyloid-beta1-42 (Aß1-42), respectively, to establish the in vivo and in vitro models of AD. The downstream genes of p75NTR were predicted by RNA-sequencing and bioinformatics analysis. Then the interaction among p75NTR, nuclear factor kappa B (NF-κB), microRNA-210-3p (miR-210-3p) and phosphoethanolamine cytidylyltransferase 2 (PYCT2) was verified, followed by analysis of their effects on cognitive behaviors and biological characteristics of hippocampal neurons of mouse with AD-like symptoms. p75NTR knockout alleviated cognitive dysfunction in mice with AD-like symptoms and reduced Aß1-42-induced hippocampal neuron damage and apoptosis. p75NTR up-regulated miR-210-3p expression by activating NF-κB, thereby limiting PCYT2 expression. PCYT2 silencing in p75NTR-/- mice promoted neuronal apoptosis and aggravated cognitive dysfunction in AD mouse models. In summary, p75NTR is capable of accelerating cognitive dysfunction in AD by mediating the NF-κB/miR-210-3p/PCYT2 axis.

Transcriptome Comparison of Brain and Kidney Endothelial Cells in Homeostasis.

Endothelial cells are heterogeneous, stemming from multiple organs, but there is still little known about the connection between the brain and kidney endothelial cells, especially in homeostasis. In this study, scRNA-seq results were obtained to compare genetic profiles and biological features of tissue-specific endothelial cells. On this basis, seven endothelial cell subpopulations were identified, two of which were upregulated genes in pathways related to stroke and/or depression, as characterized by neuroinflammation. This study revealed the similarities and distinctions between brain and kidney endothelial cells, providing baseline information needed to fully understand the relationship between renal diseases and neuroinflammation, such as stroke and depression.

Up-regulation of SETD3 may contribute to post-stroke depression in rat through negatively regulating VEGF expression.

Post-stroke depression (PSD) is one of the most familiar complications of stroke, which refers to stroke patients who have varying degrees of depression (lasts for >2 weeks). SET domain-containing 3 (SETD3) is a conserved histone H3 methyltransferase, and the role of SETD3 in some diseases is increasingly being explored. However, the effects of SETD3 in PSD remain unclear. In this study, the PSD rat model was firstly constructed by Endothelin-1 injection combined with chronic unpredictable mild stress, and we discovered that SETD3 expression was up-regulated in PSD rat model. Additionally, SETD3 knockdown relieved the depressive symptom of PSD. Moreover, SETD3 knockdown promoted proliferation and differentiation of neural stem cells (NSCs). Due to the critical role of vascular endothelial growth factor (VEGF) in antidepressant and SETD3 can negatively regulate VEGF, we speculated that SETD3 may regulate PSD progression through VEGF. Our results demonstrated that SETD3 knockdown up-regulated VEGF expression. Furthermore, SETD3 modulated the proliferation and differentiation of NSCs through regulating VEGF expression. In conclusion, our study indicated that up-regulation of SETD3 contributed to PSD progression in rats through negatively regulating VEGF expression. The findings of this work suggest that SETD3 may be a promising target for treating PSD in the future.

RNA-seq of buffalo fibroblasts over-expressed pluripotent-related genes to investigate characteristics of its preliminarily reprogrammed stage.

Induced pluripotent stem cells (iPSCs) can enhance the efficiency of buffalo genetic improvements because of their differentiation potential and proliferation ability, which are similar to those of embryonic stem cells. However, very few studies have focussed on buffalo iPSCs, and a stable induction system has not been established for buffalo somatic cell reprogramming. In this study, we constructed a PiggyBac transposon vector co-expressing buffalo OCT4, C-MYC, KLF4 and SOX2 genes (PB_OMKS) separated by the nucleotide sequence of three 2A peptides and established the buffalo foetal skin fibroblast (BFSF) cell line BFSF_OMKS. RNA-seq technology and bioinformatics analysis methods were mainly employed to perform a transcriptome analysis between BFSF and BFSF_OMKS. The results revealed that over-expression of OCT4, C-MYC, KLF4 and SOX2 in BFSFs led to the activation of reprogramming-related LIF, activin, BMP4, SMAD1/5/9 and Wnt signals. These results increased our understanding of buffalo somatic cell reprogramming mechanisms and could provide a possible theory for the selection of small-molecule cocktails to promote reprogramming.

Corrigendum: Microglia Mediate the Occurrence and Development of Alzheimer's Disease Through Ligand-Receptor Axis Communication.

[This corrects the article DOI: 10.3389/fnagi.2021.731180.].

Microglia Mediate the Occurrence and Development of Alzheimer's Disease Through Ligand-Receptor Axis Communication.

Alzheimer's disease (AD) is a common neurodegenerative disease. Its onset is insidious and its progression is slow, making diagnosis difficult. In addition, its underlying molecular and cellular mechanisms remain unclear. In this study, clustering analysis was performed on single-cell RNA sequencing (scRNA-seq) data from the prefrontal cortex of 48 AD patients. Each sample module was identified to be a specific AD cell type, eight main brain cell types were identified, and the dysfunctional evolution of each cell type was further explored by pseudo-time analysis. Correlation analysis was then used to explore the relationship between AD cell types and pathological characteristics. In particular, intercellular communication between neurons and glial cells in AD patients was investigated by cell communication analysis. In patients, neuronal cells and glial cells significantly correlated with pathological features, and glial cells appear to play a key role in the development of AD through ligand-receptor axis communication. Marker genes involved in communication between these two cell types were identified using five types of modeling: logistic regression, multivariate logistic regression, least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM). LASSO modeling identified CXCR4, EGFR, MAP4K4, and IGF1R as key genes in this communication. Our results support the idea that microglia play a role in the occurrence and development of AD through ligand-receptor axis communication. In particular, our analyses identify CXCR4, EGFR, MAP4K4, and IGF1R as potential biomarkers and therapeutic targets in AD.

Identification of an miRNA Regulatory Network and Candidate Markers for Ischemic Stroke Related to Diabetes.

PURPOSE: Type 2 diabetes mellitus (T2DM) increases the risk of ischemic stroke and poor prognosis. This study aimed to identify molecular mechanisms that are dysregulated in T2DM-associated ischemic stroke and candidate genes that might serve as biomarkers. METHODS: The top 25% variance genes in the GSE21321 and GSE22255 datasets were analyzed for coexpression. The differentially expressed mRNAs (DEmRs) between patients with T2DM or ischemic stroke and controls were analyzed. Then, the union of overlapping coexpressed genes and overlapping DEmRs was analyzed. The miRNAs differentially expressed in T2DM-associated ischemic stroke were also analyzed. CIBERSORT was used to evaluate the levels of infiltration by immune cells in T2DM-associated stroke. RESULTS: Thirteen coexpression modules were identified in T2DM and 10 in ischemic stroke, and 594 module genes were shared between the two conditions. A total of 4452 mRNAs differentially expressed between T2DM patients and controls were identified, as were 2390 mRNAs differentially expressed between ischemic stroke and controls. The 771 union genes were enriched mainly in immune-related biological functions and signaling pathways. UBE2N, TGFB3, EXOSC1, and VIM were identified as candidate markers. In addition, we identified miR-576-3p as having the most regulatory roles in both T2DM and ischemic stroke. Mast cell activation was significantly down-regulated in T2DM but up-regulated in ischemic stroke. CONCLUSION: These findings provide numerous testable hypotheses about the pathways underlying T2DM-associated ischemic stroke, which may help identify therapeutic targets.

Screening for Core Genes Related to Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD), a nervous system disease, lacks effective therapies at present. RNA expression is the basic way to regulate life activities, and identifying related characteristics in AD patients may aid the exploration of AD pathogenesis and treatment. This study developed a classifier that could accurately classify AD patients and healthy people, and then obtained 3 core genes that may be related to the pathogenesis of AD. To this end, RNA expression data of the middle temporal gyrus of AD patients were firstly downloaded from GEO database, and the data were then normalized using limma package following a supplementation of missing data by k-Nearest Neighbor (KNN) algorithm. Afterwards, the top 500 genes of the most feature importance were obtained through Max-Relevance and Min-Redundancy (mRMR) analysis, and based on these genes, a series of AD classifiers were constructed through Support Vector Machine (SVM), Random Forest (RF), and KNN algorithms. Then, the KNN classifier with the highest Matthews correlation coefficient (MCC) value composed of 14 genes in incremental feature selection (IFS) analysis was identified as the best AD classifier. As analyzed, the 14 genes played a pivotal role in determination of AD and may be core genes associated with the pathogenesis of AD. Finally, protein-protein interaction (PPI) network and Random Walk with Restart (RWR) analysis were applied to obtain core gene-associated genes, and key pathways related to AD were further analyzed. Overall, this study contributed to a deeper understanding of AD pathogenesis and provided theoretical guidance for related research and experiments.

Potential Genes and Mechanisms Linking Intracerebral Hemorrhage and Depression: A Bioinformatics-Based Study.

PURPOSE: The purpose of this study was to investigate the potential pathogenic mechanisms of post-intracerebral hemorrhage depression. METHODS: Profiles of gene expression in brain tissue of patients with intracerebral hemorrhage (ICH) or depression were downloaded from the Gene Expression Omnibus (GEO) database. We analyzed differentially expressed genes (DEGs) for the two diseases separately. With these DEGs, we conducted an enrichment analysis based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) as well as cross-talk analysis, then we identified hub bridge genes using integrated bridge landscape analysis. RESULTS: We found 131 DEGs for interaction between ICH and depression. In the enrichment analysis, we found 55 GO terms and KEGG pathways involving interacting genes of ICH and depression, and 10 GO terms and 10 KEGG pathways most significantly related to cross-talk between ICH and depression. In the integrated bridge landscape analysis, we identified 20 hub bridge genes. In further analysis, we found that hub bridge genes HLA-A, HMOX1, and JUN related to endocytosis, cell adhesion, and phagosomes may exert their effects through the dopamine (DA) system and the serotonergic pathway post-ICH depression. HLA-A may play a role in the occurrence and development of ICH and depression through immune mediation and cell adhesion. HMOX1 and JUN may participate in the mechanism by interacting with HLA-A. CONCLUSION: Through bioinformatics analysis, we identified potential hub bridge genes and pathways related to post-ICH depression. Our study provides references for further research on mechanisms on the pathogenesis of post-ICH depression.

Genes Induced by Panax Notoginseng in a Rodent Model of Ischemia-Reperfusion Injury.

Stroke is a cerebrovascular disease that results in decreased blood flow. Although Panax notoginseng (PN), a Chinese herbal medicine, has been proven to promote stroke recovery, its molecular mechanism remains unclear. In this study, middle cerebral artery occlusion (MCAO) was induced in rats with thrombi generated by thread and subsequently treated with PN. After that, staining with 2,3,5-triphenyltetrazolium chloride was employed to evaluate the infarcted area, and electron microscopy was used to assess ultrastructural changes of the neurovascular unit. RNA-Seq was performed to determine the differential expressed genes (DEGs) which were then verified by qPCR. In total, 817 DEGs were identified to be related to the therapeutic effect of PN on stroke recovery. Further analysis by Gene Oncology analysis and Kyoto Encyclopedia of Genes and Genomes revealed that most of these genes were involved in the biological function of nerves and blood vessels through the regulation of neuroactive live receptor interactions of PI3K-Akt, Rap1, cAMP, and cGMP-PKG signaling, which included in the 18 pathways identified in our research, of which, 9 were reported firstly that related to PN's neuroprotective effect. This research sheds light on the potential molecular mechanisms underlying the effects of PN on stroke recovery.

Using mRNA deep sequencing to analyze differentially expressed genes during Panax notoginseng saponin treatment of ischemic stroke.

Treatment with Panax notoginseng saponin (PNS) can prevent neurological damage in middle cerebral artery occlusion model rats to promote recovery after a stroke. However, the exact molecular mechanisms are unknown and require further study. In the present study, mRNA sequencing was employed to investigate differential gene expression between model and sham groups, and between model and PNS­treated groups. Enrichment of gene data was performed using Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes database. Hub genes were identified and networks were constructed using Cytoscape that were further verified by reverse transcription­quantitative PCR. A total of 1,104 genes of interest were found, which included 690 upregulated and 414 downregulated genes that were identified when the model was compared with the sham group. Additionally, 817 genes of interest, which included 390 upregulated and 427 downregulated genes, were identified when the PNS­treated group was compared with the model group. There were 303 overlapping genes of interest between the analysis of model to sham groups, and the analysis of model to PNS­treated groups. The top 10 genes from the 303 aberrantly expressed genes of interest included ubiquitin conjugating enzyme E2 variant 2, small ubiquitin­related modifier 1, small RNA binding exonuclease protection factor La, Finkel­Biskis­Reilly murine sarcoma virus (FBR­MuSV) ubiquitously expressed, centrosomal protein 290 kDa, DNA­directed RNA polymerase II subunit K, cullin­4B, matrin­3 and vascular endothelial growth factor receptor 2. In conclusion, these genes may be important in the underlying mechanism of PNS treatment in ischemic stroke. Additionally, the present data provided novel insight into the pathogenesis of ischemic stroke.

Intranasal insulin administration may be highly effective in improving cognitive function in mice with cognitive dysfunction by reversing brain insulin resistance.

It is well known in clinical practice that Alzheimer's disease (AD) is closely associated with brain insulin resistance, and the cerebral insulin pathway has been proven to play a critical role in the pathogenesis of AD. However, finding the most efficient way to improve brain insulin resistance remains challenging. Peripheral administration of insulin does not have the desired therapeutic effect and may induce adverse reactions, such as hyperinsulinemia, but intranasal administration may be an efficient way. In the present study, we established a brain insulin resistance model through an intraventricular injection of streptozotocin, accompanied by cognitive impairment. Following intranasal insulin treatment, the learning and memory functions of mice were significantly restored, the neurogenesis in the hippocampus was improved, the level of insulin in the brain increased, and the activation of the IRS-1-PI3K-Akt-GSK3ß insulin signal pathway, but not the Ras-Raf-MEK-MAPK pathway, was markedly increased. The olfactory bulb-subventricular zone-subgranular zone (OB-SVZ-SGZ) axis might be the mechanism through which intranasal insulin regulates cognition in brain-insulin-resistant mice. Thus, intranasal insulin administration may be a highly efficient way to improve cognitive function by increasing cerebral insulin levels and reversing insulin resistance.

Evaluation of miR-34b/c polymorphisms to the risk of ischemic stroke.

OBJECTIVES: Polymorphisms in microRNA genes are related to the risk of ischemic stroke, but the association between miR-34b/c polymorphisms and the risk of ischemic stroke has not been reported. METHODS: MiR-34b/c rs2187473 and rs4938723 polymorphisms were genotyped by Snapshot assay among 495 controls and 492 ischemic stroke patients. Expression levels of miR-34b and miR-34c were quantified by real-time PCR. Transcriptional activity of miR-34b/c promoter was measured by luciferase reporter assay. RESULTS: Rs4938723 was associated with an increased risk of ischemic stroke in our study (CC versus TT: OR = 2.34, 95% CI = 1.47-3.72, P = 0.001; C versus T: OR = 1.37, 95% CI = 1.12-1.68, P = 0.002; CC versus TT + TC: OR = 2.12, 95% CI = 1.37-3.29, P = 0.001). The expression levels of miR-34b and miR-34c were significantly downregulated in cases by contrast with controls (P < 0.05). Further analysis demonstrated that the expression levels of miR-34b and miR-34c were also downregulated in the individuals carrying rs4938723 CC genotype by contrast with that carrying TT + TC genotypes (P < 0.05). The result of luciferase reporter assay showed that rs4938723C allele decreased the transcriptional activity of miR-34b/c promoter compared with rs4938723 T allele. CONCLUSION: Our study showed a positive relation between the miR-34b/c rs4938723 polymorphism and the risk of ischemic stroke, which indicated that rs4938723 may be used for ischemic stroke prediction or therapy in the future.

Involvement of p75NTR in the effects of Aß on L-type Ca2+ channel in cultured neuronal networks.

Ca2+ overload in neurons has been implicated in Alzheimer's Disease (AD). Upregulation of Ca2+ through L-type Ca2+ channels was known to be involved in the neurodegeneration induced by amyloid-ß (Aß) peptides in AD. However, little is known about the mechanism by which upregulation of L-type Ca2+ channel currents is linked to Aß-induced neuronal toxicity. In the present study, we found that the L-type Ca2+ current in transgenic AD mice (Tg2576) neurons is greater than in wild-type (WT) neurons, and this Ca2+ channel current change were rescued in Tg2576/p75NTR+/- (p75 neurotrophin receptor) neurons. We further examined the changes in the gating of L-type Ca2+ channels following Aß42 treatment, and the results showed that the L-type Ca2+ channel current was significantly increased by Aß42 treatment in WT hippocampal neurons. Blocking or decreasing the expression of p75NTR eliminated the influence of Aß42 on the L-type Ca2+ channel current in WT hippocampal neurons. We also evaluated how Aß42 affected the voltage-dependent activation and inactivation of L-type Ca2+ channels in cultured WT neurons. The results indicated that the half-maximal activation voltage (V1/2) was left shifted, and the half-inactivation voltage (V1/2) displayed a right shift in neuron treated by Aß42. Decreasing the expression of p75NTR eliminated the effect of Aß42 on voltage-dependent activation and inactivation of the L-type Ca2+ channel. These results indicate that Aß42 changes L-type Ca2+ channel currents by modulating the channel's activation and inactivation dynamics, while decreasing p75NTR expression can remove this effect.

20S proteasome and glyoxalase 1 activities decrease in erythrocytes derived from Alzheimer's disease patients.

As a result of accumulating methylglyoxal and advanced glycation end products in the brains of patients with Alzheimer's disease, it is considered a protein precipitation disease. The ubiquitin proteasome system is one of the most important mechanisms for cells to degrade proteins, and thus is very important for maintaining normal physiological function of the nervous system. This study recruited 48 individuals with Alzheimer's disease (20 males and 28 females aged 75 ± 6 years) and 50 healthy volunteers (21 males and 29 females aged 72 ± 7 years) from the Affiliated Hospital of Youjiang Medical University for Nationalities (Baise, China) between 2014 and 2017. Plasma levels of malondialdehyde and H2O2 were measured by colorimetry, while glyoxalase 1 activity was detected by spectrophotometry. In addition, 20S proteasome activity in erythrocytes was measured with a fluorescent substrate method. Ubiquitin and glyoxalase 1 protein expression in erythrocyte membranes was detected by western blot assay. The results demonstrated that compared with the control group, patients with Alzheimer's disease exhibited increased plasma malondialdehyde and H2O2 levels, and decreased glyoxalase 1 activity; however, expression level of glyoxalase 1 protein remained unchanged. Moreover, activity of the 20S proteasome was decreased and expression of ubiquitin protein was increased in erythrocytes. These findings indicate that proteasomal and glyoxalase activities may be involved in the occurrence of Alzheimer's disease, and erythrocytes may be a suitable tissue for Alzheimer's disease studies. This study was approved by the Ethics Committee of Youjiang Medical University for Nationalities (approval No. YJ12017013) on May 3, 2017.

Analysis of transcription factor- and ncRNA-mediated potential pathogenic gene modules in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that ranks as the fourth most common cause of death in developed countries. In our study, genes differentially expressed between AD and healthy individuals were identified and used to construct protein-protein interaction (PPI) networks. The AD-related PPI network was used to identify functional modules, and enrichment analysis showed that they were significantly involved in "Alzheimer's disease", "apoptosis", and related pathways. We predicted non-coding RNAs and transcription factors that may regulate the functional modules. The expression of hub genes and transcription factors was validated in an independent data set. The results in this study provide several candidates for further research on mechanisms of AD pathogenesis.

Neuroprotective effect of salidroside against central nervous system inflammation-induced cognitive deficits: A pivotal role of sirtuin 1-dependent Nrf-2/HO-1/NF-κB pathway.

Central nervous system (CNS) inflammation occurs in cognitive dysfunctions, but the underlying mechanisms remain unclear. Here, we investigated the role of sirtuin 1 (SIRT1) and salidroside in CNS inflammation-induced cognitive deficits model. In vivo, CNS inflammation was initiated by a single intracerebroventricular injection of lipopolysaccharide (LPS). The levels of inflammatory cytokines and the capability of free radial scavenging were determined after the LPS challenge. In vivo, salidroside and nicotinamide, a SIRT1 inhibitor, were used in PC12 cell. Of note, with the treatment of salidroside, LPS-induced learning and memory impairments were effectively improved. Salidroside also remarkably inhibited the inflammatory cytokines, up-regulated the concentration of superoxide dismutase and inhibited the vitalities of malondialdehyde in serum, hippocampus, and cell supernatant. Besides, the expression of Sirt1, Nrf-2, HO-1, Bax, Bcl-2, caspase-9, and caspase-3 and the phosphorylation of AMPK, NF-κBp65, and IκBα were increased accompanying with the LPS-induced cognitive impairments, which were significantly suppressed by salidroside treatment. In PC12 cell model, nicotinamide significantly abrogated the beneficial effects of salidroside, as indicated by the antioxidant, anti-inflammatory, and antiapoptosis signaling. Together, our results showed that salidroside may be a novel therapy drug in neurodegenerative diseases, and the protective effect was involved in SIRT1-dependent Nrf-2/HO-1/NF-κB pathway.

Panax notoginseng Saponins Attenuate Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury in Human SH-SY5Y Cells by Regulating the Expression of Inflammatory Factors through miR-155.

Panax notoginseng saponins (PNS) have been widely used in China to treat stroke. Accumulating evidence has found that microRNA (miR)-155 plays critical roles in the pathology of ischemic stroke. Here we investigated whether PNS plays a protective effect against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced focal inflammation and injury in SH-SY5Y cells by regulating miR-155 expression. Treatment with PNS at a concentration less than 160 µg/mL had no effect on the proliferation of SH-SY5Y cell. In OGD/R-induced SH-SY5Y cells, 160 µg/mL PNS treatment promoted cell proliferation and cell cycle progression, as well as decreased inhibited apoptosis and miR-155 expression. However, overexpression of miR-155 attenuated the promotion effects of PNS on cell proliferation and cell cycle, apoptosis inhibition in OGD/R-induced SH-SY5Y cells. Moreover, 160 µg/mL PNS treatment decreased the levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) in OGD/R-induced SH-SY5Y cells, whereas overexpression of miR-155 reversed PNS-induced decreases in the levels of IL-1ß, IL-6, and TNF-α in OGD/R-treated SH-SY5Y cells. In conclusion, PNS attenuated OGD/R-induced injury in human undifferentiated SH-SY5Y cells by regulating the expression of inflammatory factors through miR-155.

Sirt1 protects neural stem cells from apoptosis by decreasing acetylation of histone 3K9.

OBJECTIVE: To explore the role and mechanism of Sirt1 in protecting neural stem cells (NSCs) from apoptosis. MATERIALS AND METHODS: Transfection was used to overexpress Sirt1 in rat NSCs. The effect of Sirt1 overexpression on camptothecin-induced apoptosis of NSCs was evaluated. Western blotting was used to examine the expression of Sirt1, cleaved caspase-3, and acetylated histone 3K9. RESULTS: Overexpression of Sirt1 in NSCs decreased the cleavage of caspase-3 and acetylation of histone 3K9. CONCLUSION: Sirt1 may protect NSCs from apoptosis by decreasing the acetylation of histone 3 on K9.

A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development.

Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 (DISC1), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects.