Abstract Background There is a critical need to change the treatment paradigm for mental disorders by developing interventions that are able to target specific clinical components, alter the disease course and are not merely palliative in intent. A key strategy towards this goal is to focus research on causal pathways in mental disordersPMID:35026139. However, despite considerable advancesPMID:27144355, 38104575, 36801618, connecting associational findings with causal pathways remains elusive. This is largely attributable to the absence of clinically useful biomarkers, assayable structural pathology and the technology to directly investigate putative molecular pathologies in the human brain. Moreover, disorder heterogeneity with considerable inter- and intra-individual variation of symptom profile across the disease course suggests diverse underlying disease processes. These challenges have forced attention on preclinical models but there is widespread recognition of major unmet translational needs which stymie drug target identification and validation for mental disorders. These gaps have prompted calls to integrate and synthesis information from diverse preclinical modelsPMID: 39245692and that to address this requires a collaborative multi-disciplinary approach uniting preclinical and clinical research and lived experience. We describe here the creation of an international collaborative network of preclinical psychiatric research, the Consortium of Preclinical Psychiatric Research (CPPR)PMID: 41315813. We then describe how the CPPR will use a multimodal multiomics pipeline to probe schizophrenia by synthesising information from diverse preclinical models and integrating this with clinical data to build a data commons globally accessible and interrogable through AI and machine learning approaches. We propose this will accelerate understanding of causal pathways leading to schizophrenia and subsequently other mental illness and identification of putative biomarkers and novel treatment targets. Aims & Objectives 1. To establish an international consortium of preclinical psychiatric research incorporating the full spectrum of preclinical psychiatric models including animal, cell and stem cell, clinical biological samples, imaging data and human post-mortem brain tissue. 2. With schizophrenia as an exemplar to use a multimodal multiomics pipeline to generate putative biomarkers and novel drug targets. 3. To create a globally accessible data commons of harmonised "omics" data integrated with clinical data sets. Method Animal prefrontal cortex and hippocampus samples from 544 animals from 17 models, 34 cell lines, 705 human post-mortem dorsolateral prefrontal cortex and hippocampus tissue samples and 200 clinical plasma samples covering schizophrenia and healthy controls will undergo proteomic (Orbitrap Astral mass spectrophotometry / Seer Proteograph XT) and direct RNA long-read transcriptomics (Oxford Nanopore Technologies ONT) for epigenomic and transcriptomic data. Analysis and synthesis of data will be undertaken with Australian Biocommons through the open-source Gen3 platform. Results The CPPR was established in 20246 with over 50 researchers and 14 institutions. Deep phenotyping of >1450 distinct preclinical and clinical samples relevant to schizophrenia is being undertaken to create a comprehensive and detailed map of putative pathways involved in schizophrenia. Discussion & Conclusions The CPPR presents a novel approach to bridge the translational gap in psychiatric disorders. It will create a template using schizophrenia that can be applied across mental disorders and herald a new path for fast-tracking putative biomarker and drug target identification.
S. Sundram· International Journal of Neu...· 0 citations
Abstract Background Schizophrenia is a highly heritable neurodevelopmental disorder characterised by disruptions in cortical circuitry and excitatory-inhibitory balance. Converging genetic and post-mortem evidence implicates early dysfunction of GABAergic interneurons, and transcription factor ARX plays a critical role in interneuron differentiation and migration. Mutations in ARX are associated with a spectrum of neurodevelopmental disorders, including epilepsy, autism and schizophrenia. Our laboratory identified a rare missense variant (ARX R264Q) in a female patient with schizophrenia. To investigate the developmental impact of this mutation on phenotypes relevant to schizophrenia a mouse model of the mutation that was developed using CRISPR-cas9 technology. The mouse shows behavioural and electrophysiological phenotypes relevant to schizophrenia, including disrupted sensorimotor processing and reversal learning, and social deficits coupled with altered gamma power during the aforementioned tasks. Aims & Objectives To understand how this mutation could lead to the above behavioural and electrophysiological phenotypes this study now aimed to characterise cell-type-specific transcriptional changes induced by the ArxR264Q mutation during early postnatal brain development using single-cell RNA sequencing (scRNA-seq). We sought to (i) identify transcriptionally distinct brain cell populations from WT and ArxR264Q mice, (ii) assess differential gene expression between mutant and wild-type mice within specific cell types, and (iii) define disrupted biological pathways that the identified differentially expressed genes are enriched in. We hypothesised that ArxR264Q mice would exhibit disrupted gene expression in pathways related to neuronal development, with pronounced effects in GABAergic interneuron populations. Method Whole brains from wild-type and ArxR264Q mutant mice were collected at postnatal days 3-4 and processed for multiplexed scRNA-seq using 10x Genomics technology. Data were analysed bioinformatically using Cellranger and Seurat. Cells were clustered into transcriptionally distinct populations and annotated using GPT-4o annotations. Differential gene expression was assessed within each cell type between ArxR264Q mutants and wildtypes, followed by gene set enrichment analyses to identify affected biological pathways that those differentially expressed genes act on. Results Distinct subtypes were identified in neuronal, glial and progenitor populations. Differential expression analyses revealed prominent transcriptional alterations in GABAergic interneurons, layer 4-5 excitatory neurons, developing GABAergic interneurons, and developing excitatory neurons. Enriched pathways included neurogenesis, cell migration, cell adhesion, and neuronal differentiation. Key genes implicated in interneuron migration and GABAergic function, including Cxcl12, Slc6a13, and Slc32a1, were differentially expressed in mutant mice. Additional dysregulation of developmental regulators such as Sox9, Nrp1, and Sema3a suggested broader effects on neuronal fate specification and circuit assembly. Discussion & Conclusions These findings demonstrate that the ArxR264Q mutation induces early, cell-specific transcriptional dysregulation affecting pathways critical for cortical interneuron development. This work provides mechanistic insight into how a schizophrenia-associated ARX variant may perturb early neurodevelopmental trajectories, potentially contributing to later behavioural abnormalities relevant to schizophrenia such as disrupted social behaviour, delayed reversal learning and abnormal acoustic startle, as well as disrupted neural network firing during these tasks. Future work will screen the key genes identified from this study for potentially druggable candidate targets for treating interneuronopathies commonly found in neurodevelopmental disorders.
A. Yonehara, A. Coronado, A. Gibbons et al.· International Journal of Neu...· 0 citations
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