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Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays.
Human pluripotent stem cell (hPSC)-derived neuron cultures have emerged as models of electrical activity in the human brain. Microelectrode arrays (MEAs) measure changes in the extracellular electric potential of cell cultures or tissues and enable the recording of neuronal network activity. MEAs have been applied to both human subjects and hPSC-derived brain models. Here, we review the literature on the functional characterization of hPSC-derived two- and three-dimensional brain models with MEAs and examine their network function in physiological and pathological contexts. We also summarize MEA results from the human brain and compare them to the literature on MEA recordings of hPSC-derived brain models. MEA recordings have shown network activity in two-dimensional hPSC-derived brain models that is comparable to the human brain and revealed pathology-associated changes in disease models. Three-dimensional hPSC-derived models such as brain organoids possess a more relevant microenvironment, tissue architecture and potential for modeling the network activity with more complexity than two-dimensional models. hPSC-derived brain models recapitulate many aspects of network function in the human brain and provide valid disease models, but certain advancements in differentiation methods, bioengineering and available MEA technology are needed for these approaches to reach their full potential.
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Dual developmental effects of ARX poly-alanine mutations on human cortical excitatory and inhibitory neurons.
Infantile spasms (IS), a severe childhood epilepsy with an incidence of 1.6-4.5 per 10,000 live births, often lead to lifelong intellectual disability. Up to 5% of affected males carry mutations in the Aristaless-related homeobox (ARX) gene. The lack of human-specific models for developmental epilepsy limits progress, making organoids a promising alternative. We use human cortical organoids (COs) and ganglionic eminence organoids (GEOs) to model poly-alanine expansion (PAE) mutations in ARX. PAE mutations increase cortical progenitor proliferation and accelerate early cortical development. ARX expression is upregulated in patient-derived COs at 30 days in vitro (DIV), correlating with altered cell cycle gene expression. We observe enhanced, cell-autonomous interneuron migration, which is rescued by CXCR4 inhibition. ARXPAE assembloids exhibit early network hyperactivity. These findings highlight the utility of human brain organoids in uncovering ARXPAE-driven mechanisms and represent a critical step toward developing targeted therapies for IS and related developmental epilepsies.
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ARHGAP11A maintains cortical progenitor identity through RHOA-ROCK signaling during human brain development.
Mammalian brain development involves coordinated progenitor amplification, migration, and differentiation. Apical progenitors (APs) establish the ventricular zone (VZ) and are key determinants of brain size and complexity. Rho-family guanosine triphosphatases (Rho-GTPases) regulate cytoskeletal dynamics and AP behavior, but how specific Rho GTPase-activating proteins (Rho-GAPs) influence progenitor identity and VZ architecture remains unclear. Using human forebrain organoids, we investigate the function of the Rho GAP ARHGAP11A in human corticogenesis. CRISPR-Cas9-mediated ARHGAP11A knockout reveals its essential role in maintaining VZ integrity. Loss of ARHGAP11A impairs neuroepithelial organization and randomizes mitotic cleavage-plane orientation via the RHOA-ROCK-actin axis. This leads to premature AP delamination, AP depletion, and reduced cell density and glial numbers. Pharmacological inhibition of RHOA or ROCK rescues these defects, highlighting ARHGAP11A's role in cytoskeletal remodeling to maintain cortical progenitors. Our findings establish ARHGAP11A as a critical regulator of AP identity and VZ integrity, with broad implications for human corticogenesis.
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Physiological Models of Human Neuronal Development and Disease.
Human neural network development occurs at stages inaccessible to longitudinal monitoring. By transplanting human neurons to the adult mouse brain, recent studies explore human neural circuit formation in realistic cellular and physiological environments, establishing new models for human neurodevelopmental disorders.
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Metformin Restores Mitochondrial Function and Neurogenesis in POLG Patient-Derived Brain Organoids.
Mitochondrial dysfunction and impaired neurogenesis are central to mitochondrial DNA polymerase (POLG)-related disorders, yet therapeutic options remain limited. Here, patient-derived induced pluripotent stem cell (iPSC)-based cortical organoids are used to model POLG-associated neurodegeneration and assess the therapeutic potential of metformin. Single-cell RNA-seq reveals distinct vulnerabilities in dopaminergic, glutamatergic, and GABAergic neuronal subtypes, with dopaminergic neurons exhibiting the most severe loss and mitochondrial transcriptomic deficits. Metformin treatment (250 µm, 2 months) significantly restores neuronal identity, subtype-specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increased mitochondrial mass (MTG, MTDR), and reduced oxidative stress (MitoSOX, BAX/cleaved caspase 3). Notably, mitochondrial DNA (mtDNA) copy number and the expression of mitochondrial replisome proteins (POLG, POLG2) are upregulated, indicating enhanced mitochondrial genome maintenance. Calcium measurement confirms improved neuronal excitability. Untargeted metabolomics further reveals metformin-induced metabolic reprogramming, including enrichment of the tricarboxylic acid (TCA) cycle, amino acid metabolism, and redox-related pathways. Together, these findings demonstrate that metformin enhances mitochondrial integrity and neural function across multiple neuronal subtypes and offer mechanistic insights into its potential as a treatment for POLG-related disorders.
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iPSC-derived models for anorexia nervosa research.
Anorexia nervosa (AN) is a complex neuropsychiatric disorder with genetic and epigenetic components that results in reduced food intake combined with alterations in the reward-processing network. While studies of patient cohorts and mouse models have uncovered genes and epigenetic changes associated with the disease, neuronal networks and brain areas preferentially activated and metabolic changes associated with reduced food intake, the underlying molecular and cellular mechanisms remain unknown. The use of both 2D in vitro cultures and 3D models, namely organoids and spheroids, derived from either human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), would allow identification of cell type-specific changes associated with AN and comorbid diseases, to study preferential connections between brain areas and organs, and the development of therapeutic strategies.
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Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development.
Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we developed human cortical organoids that dynamically change cellular populations during maturation and exhibited consistent increases in electrical activity over the span of several months. The spontaneous network formation displayed periodic and regular oscillatory events that were dependent on glutamatergic and GABAergic signaling. The oscillatory activity transitioned to more spatiotemporally irregular patterns, and synchronous network events resembled features similar to those observed in preterm human electroencephalography. These results show that the development of structured network activity in a human neocortex model may follow stable genetic programming. Our approach provides opportunities for investigating and manipulating the role of network activity in the developing human cortex.
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From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures.
Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.
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[Features of the effect of the sera of patients with hepatocerebral dystrophy on nerve tissue in vivo and in vitro].
Electron microscopy of normal rabbit brain, conducted after the animals had been given intracerebral injection of serum obtained from patients with hepatocerebral dystrophy revealed some peculiarities of the damaging effect of such serum on the brain. Incubation of neural tissue culture with such serum resulted in appearance of hypertrophic astrocytes, type II Alzheimer's cells and Opalski's cells combined with the intact synthesis of an astrocyte specific antigen--an acid protein of astrocytic fibrility--detected by Coons' immunofluorescent test.
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Structure of the neurosecretory system in lepidoptera. Light and electron microscopy of type A'-neurosecretory cells in the brain of normal and starved larvae of the slikworm Bombyx mori.