Cross-Platform Validation of Neurotransmitter Release Impairments in Schizophrenia Patient-Derived NRXN1-Mutant Neurons
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PROVIDER: PRJNA713833 | ENA |
REPOSITORIES: ENA
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Project description:Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and predispose to multiple other neurodevelopmental disorders. Previous studies showed that engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multi-center effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. We show that in neurons that were trans-differentiated from induced pluripotent stem cells derived from three NRXN1-deletion patients, the same impairment in neurotransmitter release was observed as in engineered NRXN1-deficient neurons. This impairment manifested as a decrease in spontaneous synaptic events and in evoked synaptic responses, and an alteration in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.
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Project description:Malfunction of multiple regions in distributed brain circuits has been suggested to underlie the diversity of symptoms and cognitive impairments in schizophrenia. The cerebellum, as part of this circuit, may contribute to these symptoms for this reason we undertook a proteomic profile of this region. Here, we design a quantitative exploratory proteomic analysis in pooled grey matter of the cerebellum from schizophrenia and control individuals with the aim of discovering consistently altered biomarker proteins in schizophrenia.
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Project description:<p>Schizophrenia is a common mental illness. It is a complex disorder with many symptoms and cognitive impairments. Despite extensive study, the molecular mechanisms of this disease are still unknown. Present time studies on the lipid composition of the human brain are extremely fragmented. Of the possible levels of molecular analysis involving gene expression at the RNA or protein level, and the representation of polar metabolites and lipids, the latter seem to us to be the most promising now. We chose lipids as representative data of the pathogenic mechanism because they are the main structural components of brain cell tissue. The dataset provided unique samples of lipid LC-MS profiles of post-mortem human brains. Samples include not only healthy individuals but also patients with schizophrenia.</p>
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Project description:Abnormal N-methyl-D-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. D-serine is an important NMDAR modulator, and to elucidate the role of the D-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and drastically reduced D-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were rescued by D-serine and the atypical antipsychotic clozapine, and were conversely, amplified by NMDAR inhibition. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Furthermore, analysis of Srr genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant serine racemase function and diminished D-serine may contribute to schizophrenia pathogenesis, and that D-serine may be a beneficial form of treatment Keywords: genetic-mutant vs. wildtype comparison
2009-09-05 | GSE13974 | GEO
Project description:The neurodevelopmental theory of schizophrenia highlights the role of early brain development in the disorder's origins. Genome-wide association studies have linked schizophrenia to genetic variations in the AS3MT gene, particularly the AS3MTd2d3 isoform. To explore this connection, we created a transgenic mouse model (AS3MTd2d3-Tg) that expresses AS3MTd2d3 in cortical neural stem cells. These mice showed enlarged ventricles and impairments in sensorimotor gating and sociability. Single-cell and single-nucleus RNA sequencing of AS3MTd2d3-Tg brains revealed imbalances in cell fate and changes in excitatory neuron composition. AS3MTd2d3 was found to localize to the centrosome, disrupting mitotic spindle orientation and differentiation in the developing neocortex and organoids. Structural analysis indicated that exposed hydrophobic residues in AS3MTd2d3 are crucial for its pathogenic function. These findings may shed light on the early pathological features of schizophrenia.
2025-10-28 | PXD057242 | JPOST Repository
Project description:Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. Understanding timepoints of disturbances during neural cell differentiation processes could lead to an insight into the development of the disorder. In this context, human brain organoids and neural cells differentiated from patient-derived induced pluripotent stem cells are of great interest as a model to study the developmental origins of the disease. Here we evaluated the differential expression of proteins of schizophrenia patient-derived neural progenitors, early neurons, and brain organoids. Using bottom-up shotgun proteomics with a label-free approach for quantitative analysis. Multiple dysregulated proteins were found in pathways related to synapses, in line with postmortem tissue studies of schizophrenia patients. However, organoids and immature neurons exhibit impairments in pathways never before found in patient-derived induced pluripotent stem cell studies, such as spliceosomes and amino acid metabolism. In conclusion, here we provide comprehensive, large-scale, protein-level data that may uncover underlying mechanisms of the developmental origins of schizophrenia.
2023-03-11 | PXD026381 | Pride
Project description:Copy number variations (CNVs) account for a substantial proportion of human genomic variation, and have been shown to cause neurodevelopmental disorders. We sought to determine the relevance of CNVs to the aetiology of schizophrenia. Whole genome, high resolution, tiling path BAC array comparative genomic hybridization (array CGH) was employed to test DNA from 91 individuals with DSM-IV schizophrenia. Common DNA copy number changes that are unlikely to be directly pathogenic in schizophrenia were identified by comparison to a reference dataset of 372 control individuals analysed in our laboratory, and a screen against the Database of Genomic Variants. The remaining aberrations were tested for inheritance from the parents, and validated with Affymetrix 250K SNP arrays or 244K Agilent oligo-arrays. Thirteen aberrations satisfied our criteria. Two of them are very likely to be pathogenic. A deletion at 2p16.3 disrupts NRXN1 and was present in an affected sibling. A de novo duplication at 15q13.1 spans APBA2. The proteins of these two genes interact directly and play a role in synaptic development and function. Both genes have been affected by CNVs in other neurodevelopmental disorders. Keywords: Array CGH
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