Project description:A missense mutation (A391T) in the manganese transporter SLC39A8 is strongly associated with schizophrenia through GWAS, though the molecular connection to the brain remains hypothetical. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a mouse knock-in model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. N-linked glycosylation was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, one third of all detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia such as cell adhesion molecules and neurotransmitter receptors. These findings provide a mechanistic link between a risk allele and biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia.
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.
Project description:Large-scale genomic screenings greatly advanced our understanding of the genetic basis of schizophrenia. However, how this translates into neurobiological functioning is not clear. Therefore, we aimed to characterize the function of robust susceptibility gene zinc finger protein 804A (ZNF804A), using a model system of relevant cell type and neurodevelopmental timepoint. Based on previous findings, we hypothesized a role for ZNF804A in local protein translation. CRISPR/Cas9-mediated mutation of the risk gene led to increased synapse formation in human induced pluripotent stem cell (hiPSC)-derived developing glutamatergic forebrain neurons as assessed by high-content confocal imaging. Further, mass spectrometry analysis showed an increased recruitment of ribosomes to mutation neurites. Surface sensing of translation (SUnSET) screening complemented this by demonstrating an increased efficiency of local protein synthesis. Overall, these results introduce a novel cellular function for ZNF804A in a model system relevant to schizophrenia, uncovering some aspects of its neurobiology. Ultimately, findings of this study may aid to identify common mechanisms of susceptibility genes.
Project description:The study reports brain proteomic alterations in a chronic ketamine-induced mouse model of schizophrenia characterized by anxiety and cognitive impairment.
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.
Project description:Recent studies have identified presynaptic increase in striatal dopamine as the primary dopaminergic abnormality in schizophrenia, responsible for changes in cortical dopamine function in schizophrenic individuals. However, increased dopamine synthesis and release are not recapitulated in existing mouse models, limiting studies on disease progression and potential treatments. We found that the levels of glial cell line-derived neurotrophic factor (GDNF), a strong dopamine system modulator, are increased in the cerebrospinal fluid of first episode psychosis patients. Using a novel strategy to conditionally increase endogenous gene expression, we developed a mouse model with timed elevation of endogenous GDNF. Conditional ‘Knock Up’ of endogenous GDNF expression (GDNF cKU) in the central nervous system at midgestation resulted in an increase of dopamine levels in the presynaptic compartment of nigrostriatal dopamine neurons, hypodopaminergia in the prefrontal cortex (PFC) and schizophrenia-like behavioural deficits in the mouse. RNA sequencing from the PFC revealed gene expression changes similar to those previously found in schizophrenia patients, including downregulation of dopamine receptor 2 and adenosine A2a receptor (A2AR). Treatment of mice with A2AR antagonist istradefylline partially restored striatal and cortical dopamine levels, suggesting a potential therapeutic strategy to alleviate symptoms associated with schizophrenia. Taken together, our results demonstrate that timed increase in GDNF expression is sufficient to drive schizophrenia-like molecular and behavioural phenotypes, and represents a novel model for studying schizophrenia-associated pathologies in mice.
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