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Convergence of schizophrenia risk genes on CALN1 disrupts human forebrain development and drives core psychotic behaviors including hallucination-like perception.
BACKGROUND: Schizophrenia, a highly heritable neurodevelopmental disorder characterized by core clinical symptoms such as hallucination, remains poorly understood its polygenic pathogenesis. METHODS: We selected 11 key schizophrenia risk genes and generated single-gene-knockout-precise-dorsal/ventral-forebrain-organoids via CRISPR-Cas9 system to investigate the polygenic effects of these schizophrenia risk genes on forebrain development via bulk and scRNA-sequencing, multi-electrode array recording and knockout mouse model. RESULTS: We found that knockout of 11 risk genes leads to different levels of deficits in human dorsal/ventral forebrain organoids. Notably, CALN1 knockout significantly impacted pathways involved in forebrain development and the set of prioritized schizophrenia risk genes. Importantly, Caln1-KO mice exhibited a broad spectrum of schizophrenia-like behaviors, encompassing deficits in spatial memory, social ability and pre-pulse inhibition, alongside spontaneous startle behavior, head-twitch response and hallucination-like perception. At the cellular level, Caln1-deficient mice exhibit abnormal spontaneous abrupt burst spiking in mature layer-5 pyramidal neurons of the prefrontal cortex, and snRNA-seq analysis of Caln1-/- mice revealed severe transcriptional and gene network dysregulation in layer-5 excitatory neurons. CONCLUSIONS: This study reveals that CALN1 as a pivotal role in schizophrenia risk genes robustly perturb human forebrain development and cause a broad spectrum of schizophrenia behaviors in mice.
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Review of functional in vitro models of the blood-cerebrospinal fluid barrier in leukaemia research.
Acute lymphoblastic leukaemia represents the most common paediatric malignancy. Although survival rates approach up to 90% in children, investigation of leukaemic infiltration into the central nervous system (CNS) is essential due to the presence of ongoing fatal complications. Recent in vitro studies mostly employed models of the blood-brain barrier (BBB), as endothelial cells of the microvasculature represent the largest surface between the blood stream and the brain parenchyma. However, crossing the blood-cerebrospinal fluid barrier (BCSFB) within the choroid plexus (CP) has been shown to be a general capability of leukaemic blasts. Hence, in vitro models of the BCSFB to study leukaemic transmigration may be of major importance to understand the development of CNS leukaemia. This review will summarise available in vitro models of the BCSFB employed to study the cellular interactions with leukaemic blasts during cancer cell transmigration into the brain compartment across primary or immortal/immortalised BCSFB cells. It will also provide an outlook on prospective improvements in BCSFB in vitro models by developing barrier-on-a-chip models and brain organoids.
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Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation.
The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound 1 led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved in vitro safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor 11 demonstrated strong in vivo target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound 11 enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis.
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Cell type-agnostic transcriptomic signatures enable uniform comparisons of neural maturation.
Understanding where a cell sits along developmental time is as important as identifying its type. While single-cell transcriptomics has catalogued the diversity of neural cell types, aligning them along a shared temporal axis across studies, species, and model systems remains a fundamental challenge. Here, we develop a single-cell transcriptomic 'clock' that predicts true developmental age, enabling standardized, cross-context comparisons of neural maturation. Through a meta-analysis of over 2.8 million cells from the developing human brain, we identify robust tissue-level and cell-autonomous predictors of developmental age. We find that bulk tissue composition predicts age within individual studies but lacks generalizability, whereas specific cell type proportions, particularly astrocytes and progenitors, track age reliably across studies. Using machine learning, we develop a cell type-agnostic predictor based on 462 genes that robustly tracks developmental dynamics across diverse cell types and datasets (error = 2.6 weeks). Our model accurately estimates developmental age in human neural organoids and detects disease-associated shifts. Model predictions further generalize across species, revealing 10-fold accelerated neurodevelopment in mice relative to humans. Our approach provides a robust framework to assess neural maturation across contexts, with broad relevance for developmental biology and disease modeling.
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A Study on the Inflammatory Response of the Brain in Neurosyphilis.
Neurosyphilis (NS) is a clinical condition caused by infection of the central nervous system (CNS) by Treponema pallidum (Tp) that can lead to asymptomatic meningitis and more serious neurological diseases, such as dementia and blindness. However, current studies on the pathogenesis of NS are limited. Here, through the integration analysis of proteomics and single-cell transcriptomics, Toll-like/NF-κB signaling is identified as the key pathway involved in CNS damage caused by Tp. Moreover, monocyte-derived macrophages are key cells involved in the inflammatory response to Tp in the CNS of NS patients. In addition, it is found that inflammatory cells in peripheral blood may cause neurological damage through disruption of the blood‒brain barrier (BBB) in individuals with NS. Notably, activation of the Toll-like/NF-κB signaling pathway, as well as dysregulation of neural function, is likewise validated in an in vitro NS brain organoid model. In conclusion, the results revealed the mechanisms of inflammation-mediated brain injury in Tp-induced NS and provided new ideas for the clinical treatment of Tp infection.
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A Magnetically Powered Stem Cell-Based Microrobot for Minimally Invasive Stem Cell Delivery via the Intranasal Pathway in a Mouse Brain.
Targeted stem cell delivery with microrobots has emerged as a potential alternative therapeutic strategy in regenerative medicine, and intranasal administration is an effective approach for minimally invasive delivery of therapeutic agents into the brain. In this study, a magnetically powered stem cell-based microrobot ("Cellbot") is used for minimally invasive targeted stem cell delivery to the brain through the intranasal passage. The Cellbot is developed by internalizing superparamagnetic iron oxide nanoparticles (SPIONs) into human nasal turbinate stem cells. The SPIONs have no influence on hNTSC characteristics, including morphology, cell viability, and neuronal differentiation. The Cellbots are capable of proliferation and differentiation into neurons, neural precursor cells, and neurogliocytes. The Cellbots in the microfluidic channel can be reliably manipulated by an external magnetic field for orientation and position control. Using an ex vivo model based on brain organoids, it is determined that the Cellbots can be transplanted into brain tissue. Using a murine model, it is demonstrated that the Cellbots can be intranasally administered and magnetically guided to the target tissue in vivo. This approach has the potential to effectively treat central nervous system disorders in a minimally invasive manner.
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Impact of micro- and nanoplastics exposure on human health: focus on neurological effects from ingestion.
Microplastics (MPs) and nanoplastics (NPs) have become pervasive contaminants in food, water, and air, leading to widespread human exposure, primarily through ingestion. Although MPs are increasingly detected in human tissues, including the placenta, blood, and brain, their long-term health implications are poorly understood. This review compiles emerging evidence on the systemic distribution and biological effects of ingested MPs, particularly on neurological risks. MPs can disrupt gut microbiota, breach intestinal and blood-brain barriers, and accumulate in neural tissues. Mechanistic studies reveal that MPs induce oxidative stress, neuroinflammation, protein aggregation, and neurotransmitter alterations, which may contribute to the development of cognitive dysfunction and neurodegenerative disease pathways. Recent work using brain organoids, single-cell and multi-omics technologies provides deeper mechanistic insights, linking MP/NP exposure to mitochondrial injury, inflammatory signaling, and impaired protein homeostasis. We also identify important gaps in exposure assessment, NPs detection, and epidemiological evidence. Human studies remain scarce but initial reports associating elevated MP/NP burdens in brain tissue with dementia highlight the urgency of this research. To address these gaps, we suggest critical next steps in the research agenda, integrating omics technologies, real-world exposure models, and human-relevant in vitro systems. As MP contamination grows, it is critical to understand its neurotoxic potential for informing public health policy and protecting vulnerable populations.
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Investigating Mitochondrial Bioenergetics in Intact Heart and Brain Tissue Slices.
Mitochondria are essential for maintaining the high energetic demands of the heart and brain, generating ATP required for contractile function, neuronal signaling, and ionic homeostasis. In both tissues, metabolic flexibility is critical for maintaining bioenergetic efficiency, redox balance, and cellular viability. Despite their importance, existing experimental approaches to assess mitochondrial bioenergetic function present notable limitations. Isolated mitochondria and permeabilized cell assays provide precise control over substrates and respiratory states but disrupt organelle integrity and remove native cellular and extracellular context. Conversely, measurements in isolated or cultured cells preserve intact mitochondria but introduce phenotypic and metabolic artifacts. These constraints highlight the need for an intermediate platform that preserves native tissue architecture and cellular diversity while enabling quantitative assessment of mitochondrial bioenergetics. Building on prior demonstrations of respiration measurements in intact cardiac and neural tissue, we describe a tissue punch-based approach that enables region-specific analysis of mitochondrial function in small ex vivo tissue slices of intact heart and brain. This method preserves cytoarchitecture, and intercellular interactions while remaining compatible with high-resolution Seahorse respirometry analysis. Tissue punches allow multiple technical replicates from individual organs, reduce variability associated with isolation procedures, and enable assessment of regional metabolic heterogeneity, such as atrial versus ventricular myocardium or discrete brain regions. Here we present detailed and reproducible workflow protocols for brain and cardiac tissue punch preparation and extracellular flux analysis, including guidance on sample acquisition, punch sizing, normalization strategies, and data interpretation, with considerations for adapting the protocols across multiple pre-clinical models. © 2026 Wiley Periodicals LLC. Support Protocol: Preparation, Reagent Setup, and Instrumentation Basic Protocol 1: Cardiac tissue preparation Basic Protocol 2: Brain tissue preparation: rodents Basic Protocol 3: Brain tissue preparation: nonhuman primates Basic Protocol 4: Placement of tissue punches on Seahorse organoid plate Basic Protocol 5: Mitochondrial respiration measurements Basic Protocol 6: Tissue disruption for total protein quantification.
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Molecular hallmarks of hydrocephalus.
Hydrocephalus (HC) is a failure of brain and cerebrospinal fluid (CSF) homeostasis often associated with dilation of the CSF-filled ventricles (ventriculomegaly). Hallmarks of HC include aberrant CSF dynamics, neural stem cell dysfunction resulting in impaired neurogenesis and corticogenesis, biomechanical instability at the brain-CSF interface, and disrupted synaptogenesis and neural circuitry. Pleiotropic mechanisms, including genetic and environmental insults to the brain, contribute to neurodevelopmental comorbidities. Hypothesis generation from genome-wide, single-cell multi-omic analyses coupled to experimental validation using induced pluripotent stem cell-derived cerebral organoids will refine molecular classification of HC subtypes and may lead to precision-based surgical and pharmacologic treatments.
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From Young to Old: AMPylation Hits the Brain.
Protein post-translational modifications (PTMs) are implicated in numerous physiological processes and significantly contribute to complex regulatory networks of protein functions. Recently, a protein PTM called AMPylation was found to play a role in modulation of neurodevelopment and neurodegeneration. Combination of biochemical and chemical proteomic studies has uncovered the prevalence of this PTM in regulation of diverse metabolic pathways. In metazoans, thus far two protein AMP transferases have been identified to introduce AMPylation: FICD and SELO. These two proteins were found to be involved in unfolded protein response and redox homeostasis on the cellular level and in the case of FICD to adjust the development of glial cells and neurons in Drosophila and cerebral organoids, respectively. Together with findings on AMPylation and its association with toxic protein aggregation, we summarize in this Perspective the knowledge and putative future directions of protein AMPylation research.