Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: implications for schizophrenia
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ABSTRACT: We characterized the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which model the hemi-deletion we found in human subjects with schizophrenia, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity compared to wildtype (WT) mice. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood of the HET mice compared to WT mice.
Project description:Methylglyoxal (MG) is a reactive alpha-dicarbonyl by-product of glycolysis. Several bio-defense systems to detoxify the highly toxic MG are equipped in our body, including an enzymatic system by glyoxalase (GLO) 1 and GLO2 and a scavenge system by vitamin B6 (VB6). We have reported that some population of patients with schizophrenia shows impairment of the MG detoxification systems. Although we have evidences showing a link between impairment of MG detoxification systems and development of schizophrenia, the molecular mechanism to connect them remains poorly understood. Here, we generated a novel mouse model for MG detoxification deficits by feeding Glo1 knockout mice with VB6-lacking diets (KO/VB6(-)), and evaluate effects of impaired MG detoxification systems on brain function. KO/VB6(-) mice showed the accumulation of MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed schizophrenia-like behavioral deficits, such as social deficits, cognitive impairment, a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-seq and weighted gene correlation network analysis (WGCNA). Finally, we actually demonstrated respiratory deficits in mitochondria isolated from the PFC of KO/VB6(-) mice. These findings suggest that MG detoxification deficits might cause schizophrenia-like behavioral deficits via mitochondrial dysfunction in the PFC.
Project description:We report that colonic lamina propria anti-inflammatory macrophages from Il10rb-/- (KO) mice at 12 weeks possessed significantly high levels of proinflammatory transcripts compared to the ones from Il10rb+/- (het) controls. While the transcriptional profile between macrophages from KO and het mice was comparable at 1 weeks and did not possess significant levels of proinflammatory transcripts, we show that the macrophages from KO mice were enriched for proinflammatory transcripts at 3 weeks compared to the ones from 3 week old het controls. These data indicate that the anti-inflammatory signature of colonic lamina propria macrophages from Il10rb-/- mice is compromized at 3 weeks.
Project description:Purpose: The goal of this study is to detect differentially expressed genes, between Nicol +/- (Nicol-Het), Nicol-/- (Nicol-KO), and Ros1-/- (Ros1-KO) caput epididymis by RNA sequencing Methods: Caput epidiymal mRNA profiles of 14-week-old Nicol-Het, Nicol-KO, and Ros1-KO mice were generated by deep sequencing, in triplicate, using Illumina NovaSeq6000. Results: RNA-seq data identified differentially expressed transcripts. Conclusions: Our results show that the expression of many genes were downregulated in Nicol-KO caput epididymis compared with Nicol-Het one. The gene downregulation of Nicol-KO caput epididymis was similar to that of Ros1-KO one.
Project description:To investigate the roll of ARID1A in the regulation of effector CD8+ T cell responses, we crossed GzmB-Cre P14 Thy1.1 mice with Arid1a-fl/fl mice to generate Arid1a Het and KO mice. We then performed gene expression profiling analysis of WT, Het, and KO cells in vivo at d3, d5, and d8 post-LCMV Armstrong infection.
Project description:Summary: Spinal cord injury (SCI) is a damage to the spinal cord induced by trauma or disease resulting in a loss of mobility or feeling. SCI is characterized by a primary mechanical injury followed by a secondary injury in which several molecular events are altered in the spinal cord often resulting in loss of neuronal function. Analysis of the areas directly (spinal cord) and indirectly (raphe and sensorimotor cortex) affected by injury will help understanding mechanisms of SCI. Hypothesis: Areas of the brain primarily affected by spinal cord injury are the Raphe and the Sensorimotor cortex thus gene expression profiling these two areas might contribute understanding the mechanisms of spinal cord injury. Specific Aim: The project aims at finding significantly altered genes in the Raphe and Sensorimotor cortex following an induced moderate spinal cord injury in T9.
Project description:We report the genome-wide binding sites of the NK homeodomain transcription factor, Nkx3-1, in mouse prostate. Three different mouse genotypes were used: Nkx3-1 wild-type (WT), Nkx3-1 heterozygote (HET), and Nkx3-1 knock-out (KO). Two biological replicates were performed for WT and HET, and one replicate for KO. The mice used were a recombinant inbred C57BL6/J x 129 strain. The KO dataset was used as a control in lieu of an IgG. Examination of Nkx3-1 binding sites in Nkx3-1+/+ (WT), +/- (HET) and -/- (KO) mouse prostates
Project description:To investigate the role of ARID1A in the regulation of effector CD8+ T cell responses, we crossed GzmB-Cre P14 Thy1.1 mice with Arid1a-fl/fl mice to generate Arid1a Het and KO mice. We then performed chromatin accessibility profiling analysis by ATAC-seq in WT, Het, and KO cells in vivo at d0, 48h in vitro activated, d3, d5, and d8 post-LCMV Armstrong infection.
Project description:As part of collaboration between UCLA and CHDI, UCLA is creating knockouts (KOs) of 123 genes, implicated in Huntington’s disease (HD) through various computational modeling efforts. Striatum and cortex were isolated from 12-month-old Msh2-/- (KO) or Msh2+/-mice crossed with the Rgs9+/- and Q140 knock-in (KI) HD mice and their respective controls. Transcriptomic analysis (RNASeq) was performed on 9 genotypes: WT, Msh2-/-, Rgs9+/- X Msh2-/-, Rgs9+/-, Het (Q140) KI X Msh2-/-, Het (Q140) KI X Rgs9+/- X Msh2+/-, Het (Q140) KI X Rgs9+/- X Msh2-/-, Het (Q140) KI X Rgs9+/-, and Het (Q140) KI, 6-8 replicates per genotype.
Project description:Mice with homozygous null mutations in the HDL receptor (SR-BI) and apoE genes (SR-BI KO/apoE double KO (dKO) mice) spontaneously develop occlusive, atherosclerotic coronary artery disease (CAD) and die prematurely (50% mortality at 42 days of age) on standard chow diet feeding. Microarray analysis was performed to investigate the changes in gene expression profiles during the development of spontaneous severe CAD, which includes myocardial infarction and heart failure. These data will provide new insights in understanding the pathophysiology of CAD. The whole Hearts from dKO or SR-BI+/- apoE-/- (HET) mice (n=9-12) were harvested at 21, 31 and 43 days of age, and analyzed using Affymetrix microarrays. dKO mice do not show detectable signs of CAD at 21 days of age, small myocardial infarction (MI) and heart failure at 31 days of age, and extensive MI and severe heart failure at 43 days of age (50% mortality at 42 days of age). Each mouse was assigned to one array. SR-BI+/- apoE-/- mice (HET) which do not develop detectable signs of CAD on chow diet were used as controls.The data also include those from probucol treated dKO and HET mice (n=2-8).
Project description:We report the genome-wide binding sites of the NK homeodomain transcription factor, Nkx3-1, in mouse prostate. Three different mouse genotypes were used: Nkx3-1 wild-type (WT), Nkx3-1 heterozygote (HET), and Nkx3-1 knock-out (KO). Two biological replicates were performed for WT and HET, and one replicate for KO. The mice used were a recombinant inbred C57BL6/J x 129 strain. The KO dataset was used as a control in lieu of an IgG.