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Brain transcriptome profiling in wildtype mice and mice with Igf2 enhancer deletion (Igf2enh-/-) [RNA-seq]

ABSTRACT: Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. We report the first multi-omics study of neurons isolated from the prefrontal cortex of individuals with schizophrenia and bipolar disorder, including genome-wide neuronal DNA methylation using Illumina EPIC microarrays, transcriptomes and SNP genotypes (n=55 cases and 27 controls). Epigenetic, transcriptomic, and genetic-epigenetic interactions in disease converged on pathways of neurodevelopment, synaptic activity, and immune functions. Notably, we discovered prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in neurons of major psychosis patients. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene, which is responsible for dopamine synthesis. IGF2 enhancer hypomethylation was associated with increased TH protein levels in the human brain. The Igf2 enhancer was deleted in mice to explore the transcriptomic and proteomic consequences of this genomic locus in the frontal cortex and striatum. In mice, Igf2 enhancer deletion disrupted levels of TH protein and striatal dopamine, as well as induced transcriptional and proteomic abnormalities affecting development and synaptic function. Epigenetic control of the IGF2 enhancer may regulate dopamine levels and contribute to psychosis risk.

OTHER RELATED OMICS DATASETS IN: PXD012786

ORGANISM(S): Mus musculus

PROVIDER: GSE120423 | GEO | 2019/05/03

REPOSITORIES: GEO

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Synaptosome proteome IGF2 enhancer knockout mice

Project description:We identified an enhancer element near IGF2 locus that is possibly involved with dopamine function and schizophrenia. A knockout mouse was generated for the enhancer element in the IGF2 locus. We then characterized the striatal synaptosomes ( i.e. biological fraction representing pre- post synaptic nerve terminal)by mass spectometry from WT and Igf2 enhancer KO mice.

2019-05-31 | PXD012786 | Pride

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Project description:Among the fundamental unresolved questions in psychiatry is why symptoms of psychosis, such as auditory hallucinations in schizophrenia, fail to appear until early adulthood. Here we report that in mouse models of 22q11.2 deletion syndrome (22q11DS), a leading genetic cause of schizophrenia, synaptic transmission at thalamocortical inputs to the auditory cortex becomes disrupted later in life, thereby recapitulating the adult onset of psychosis. Age-dependent disruption of thalamocortical synaptic transmission in 22q11DS is mediated by dopamine receptor Drd2-targeting microRNA miR-338-3p, which is enriched in the thalamus but becomes depleted due to haploinsufficiency of the microRNA-processing 22q11DS gene Dgcr8. Deletion/knockdown of miR-338-3p causes the Drd2 increase in the auditory thalamus and abnormal sensitivity of 22q11DS thalamocortical inputs to antipsychotics, replicates auditory synaptic and behavioral abnormalities in 22q11DS, and eliminates age dependence of these auditory deficits. These results suggest that miR-338-3p mediates the pathogenic mechanism of 22q11DS-related psychosis and controls its late onset.

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2021-11-29 | PXD027667 | Pride

Heterozygous Hnrnph1 deletion decreases methamphetamine reinforcement, reward, and dopamine release and opposing changes in synaptosomal mitochondrial protein levels

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Project description:Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d=2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.

2021-02-16 | GSE138802 | GEO

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