Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and behavioral deficits
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ABSTRACT:
PROVIDER: PRJNA629318 | ENA |
REPOSITORIES: ENA
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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.
2021-07-20 | GSE149585 | GEO
Project description:The human 16p11.2 gene locus is a hot spot for copy number variations, which predispose carriers to a range of neuropsychiatric phenotypes. Microduplications of 16p11.2 are associated with autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia (SZ). Despite the debilitating nature of 16p11.2 duplications, the underlying molecular mechanisms remain poorly understood. Here we performed a comprehensive behavioral characterization of 16p11.2 duplication mice (16p11.2dp/+) and identified social and cognitive deficits reminiscent of ASD and ID phenotypes. 16p11.2dp/+ mice did not exhibit the SZ-related sensorimotor gating deficits, psychostimulant-induced hypersensitivity, or motor impairment. Electrophysiological recordings of 16p11.2dp/+ mice found deficient GABAergic synaptic transmission and elevated neuronal excitability in the prefrontal cortex (PFC), a brain region critical for social and cognitive functions. RNA-sequencing identified genome-wide transcriptional aberrance in the PFC of 16p11.2dp/+ mice, including downregulation of the GABA synapse regulator Npas4. Restoring Npas4 expression in PFC of 16p11.2dp/+ mice ameliorated the social and cognitive deficits and reversed GABAergic synaptic impairment and neuronal hyperexcitability. These findings suggest that prefrontal cortical GABAergic synaptic circuitry and Npas4 are strongly implicated in 16p11.2 duplication pathology, and may represent potential targets for therapeutic intervention in ASD.
2020-07-27 | GSE155131 | GEO
Project description:In our study, we investigated the effect of methylglyoxal on metabolic, transcriptomic, metabolomic and proteomic profiles in the context of the development of kidney impairment in an experimental model of metabolic syndrome. Dicarbonyl stress was induced in experimental group by intragastrical administration of methylglyoxal (3x/ week in dose 0.5 mg/kg b.wt.for 4 weeks) in a strain of hereditary hypertriglyceridaemic rats (HHTg). Transcriptome assessment in kidney cortex was performed in 8 male adult rats of experimental group and compared to that of 6 age- and sex- matched rats of control group.
2020-02-08 | E-MTAB-7690 | biostudies-arrayexpress
Project description:The interior of the eukaryotic cell nucleus is a highly organized 3D structure. In mature hippocampal and cortical pyramidal neurons, transcriptionally silent DNA is typically compacted in a few clusters referred to as chromocenters that are strongly stained with DNA intercalating agents like DAPI and whose function is still uncertain. We found that this 3D structure was severely disrupted by the incorporation of the chimeric histone H2BGFP into neuronal chromatin. Experiments in inducible and forebrain restricted bitransgenic mice demonstrated that the expression of this histone alters the higher-order organization of neuronal heterochromatin and causes a complex behavioral phenotype that includes hyperactivity, and social interaction, prepulse inhibition and cognitive defects. This phenotype was associated with highly specific transcriptional deficits that affected several serotonin receptor genes located at the edge of gene desert regions. Pharmacological and electrophysiological experiments indicate that this epigenetically-induced hyposerotonergic state may underlie the behavioral defects. Our results suggest a new role for perinuclear heterochromatin and chromocenter organization in the epigenetic regulation of neuronal gene expression and mental illness. We used microarrays to detect differential gene expression in transgenic mice expressing histone H2BGFP in the forebrain. We obtained triplicate samples (biological replicates) of either genotype (wild-type and H2BGFP mice). Each sample contained pooled total RNA from the hippocampi of 2 three-month old genotype-matched mice.
2014-07-18 | E-GEOD-48437 | biostudies-arrayexpress
Project description:Epigenetic Treatment of Behavioral and Physiological Deficits in a Tauopathy Mouse Model
| PRJNA755255 | ENA
Project description:Gut Microbiota from Human Autism Spectrum Disorder Induces Behavioral Deficits in Mice
| PRJNA432094 | ENA
Project description:Dravet Syndrome (DS) is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. While different therapeutic strategies based on the upregulation of the healthy gene copy are being developed, repetitive seizures might lead to endurable and hardly treatable neural deficits. In fact, whether and to which extent this severe pathology is reversible after symptom onset remains unknown and the lack of this knowledge prevents the development of more effective therapies. We generated a novel Scn1a conditional knock-in mouse model (Scn1aStop) where Scn1a expression could be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with SUDEP and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene reconstitution when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures and marked amelioration of behavioral abnormalities. Normalization of firing of hippocampal parvalbumin interneurons was observed after reactivation of the Scn1a mutant allele. We also identified dramatic gene expression alterations associated with astrogliosis in DS mice, rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological levels rescued epileptic seizures also in adult DS mice (P90) after months of repetitive seizure events. These results uncover the principles governing the reversibility of a severe epileptic encephalopathy as DS and they are central for accelerating therapeutic translation, providing key insights on the timing of delivery of the disease modifying therapies in DS.
2021-11-29 | GSE171191 | GEO
Project description:While the exact mechanisms for a sex bias in the development of neuropsychiatric disorders remain only vaguely understood, there is increasing evidence that an early life immune activation contributes to the disease pathogenesis. By administering the double stranded RNA analogue polyriboinosinic:polyribocytidilic acid (poly(I:C)) we mimicked an early viral infection in neonatal female and male mice. As a consequence, male adolescent mice presented long-term behavioral deficits including impaired social behavior and defective spatial working and recognition memory. Notably, behavioral changes were completely absent in female mice. In male mice, poly(I:C) led to an increased number of infiltrating T cells in the brain parenchyma, an enhanced interferon-g (IFNg) signaling, and an epigenetic reprogramming of microglial cells. These reprogrammed microglial cells showed increased phagocytic activity, which resulted in the excessive loss of dendritic spines in male mice only. We corroborated these findings in a murine neonatal infection of mice with murine cytomegalovirus (MCMV) and found sustained aversive behavioral effects and a lower number of excitatory synapses within the hippocampal brain region in young adult male, but not in female mice. Together, our results highlight the crucial role of the early postnatal period for normal brain development: identical immune stimulation during this period led to distinct sex-specific long-term behavioral deficits, indicating that sex is potentially an underappreciated factor when investigating neuropsychiatric disorders.
2023-03-24 | GSE147443 | GEO
Project description:Despite the predominance and high heritability of Attention-Deficit/Hyperactivity Disorder (ADHD), its etiology remains elusive. Preclinical and clinical evidence partly points to impaired limbic system function, particularly that of the hippocampus (HPC). Children diagnosed with ADHD often struggle with deficits in executive function, temporal processing, and visuospatial memory, the defining hallmarks of the predominantly inattentive presentation (ADHD-PI), thought to be subserved by the HPC brain region. However, the specific genes/proteins involved and how they shape the hippocampal makeup to influence ADHD behavior are poorly understood. As an exploratory tool, hippocampal tissues from a mouse model overexpressing thyroid hormone-responsive protein (THRSP), with defining characteristics of ADHD-PI presentation, were utilized for proteomic analyses. Results revealed differential expressions of proteins involved in Wnt signaling. Compared to THRSP knockout (KO), THRSP OE mice have impaired attention and memory concomitant to dysregulated Wnt signaling affecting hippocampal cell proliferation (BrdU) and neurogenic markers expressions (i.e., NEU-N, GFAP), markers of neural stem cell (NSC) activity. Also, exposure to a combination of enriched environment and treadmill exercise improves behavioral deficits in THRSP OE mice and improves Wnt signaling and NSC activity.
2023-01-18 | PXD038525 | Pride
Project description: Not available
| S-EPMC8068291 | biostudies-literature