Topic: human induced pluripotent stem cells

Astrocytes are crucial mediators of brain function on a multimodal level such as energy metabolism or synapse formation and maturation. They form a vast network in the brain and signal both with each other and with neurons. Calcium is the primary information carrier in astrocytes and can be measured using fluorescent indicators. Therapeutic approaches for cognitive diseases are commonly designed to influence neurons, but neglect astrocytes, despite them accounting for half the mass of the brain.Here we use astrocytic calcium signals and recent advances in analysis to develop an astrocytic comp

The dysfunction or disruption of the blood-brain barrier (BBB) has been associated with the development and progression of many neurodegenerative diseases, such as Alzheimer’s Disease (AD). However, most in vitro BBB models are static, complicating the understanding of disease pathophysiology. With that, our study aims to develop a microfluidic device to better study the relationship between neurodegenerative diseases and the BBB in vitro. The device, printed using polydimethylsiloxane, includes a compartment for a hydrogel containing neurons and astrocytes to mimic cerebral parenchyma and a m

The advent of large-scale and high-density ex-vivo experiments enables the unveiling of neural network dynamics at unprecedented resolution. It is now routinely possible to grow neural network cultures from individual human subjects, allowing us to compare the dynamics of subtly different genetic backgrounds. As the analysis of network dynamics becomes more fine-grained, we observed unexplained variability of our results during the development stages of the cultures, beyond the boundaries of genotypic differences. Our work leveraged breakthroughs in culturing cortical neurons from human induce

The aim of this work is to analyze the roles of the adaptor protein p140cap in human nervous system, at neuronal and synaptic levels, using induced neurons from human induced pluripotent stem cells (iPSCs). Studies on mice models have demonstrated how p140cap is involved in the regulation of synaptic functions, especially in the maturation, stabilization, and remodeling of dendritic spines. This protein is also implicated in plasticity phenomena, such as LTP, LTD, learning, and memory, due to its direct interaction with the GLUN2A subunit of NMDAR. The p140cap protein is encoded by the SRCIN1

In the brain, the neuronal activity is kept and controlled by a precise and well-defined “Excitatory/Inhibitory balance” among neurons, which holds importance in neurodegenerative and neurodevelopmental disorders. With the final aim of generating a reliable in vitro system of the human brain, this work was focused on the interplay between excitatory (E) and inhibitory (I) neurons in neural networks derived from human induced pluripotent stem cells (hiPSCs), deepening the critical role of heterogeneity. We exploited high-density Micro-Electrode Arrays (MEAs, 2304 electrodes) to explore two neur

Mutations in SYNGAP1 gene represent one of the most frequent genetic causes of neurodevelopmental disorders. De novo heterozygous SYNGAP1 variants are associated with a complex clinical presentation, characterized by intellectual disability, epileptic encephalopathy, hyperactivity, sleep and language disorder, and autism spectrum disorder. The SynGAP protein is highly expressed in excitatory neurons and localized mainly to synapses as a core post-synaptic density protein. Here, it acts as a potent regulator of the RAS/ERK signalling pathway, regulating synaptic plasticity and neuronal homeosta

The modern world is increasingly dependent upon artificial intelligence and machine learning. Applications range from decision-making in areas such as health and finance to autonomous vehicle control. However, current deep-learning machines and neural network algorithms have important limitations, namely ineffective learning rules, long training, and high power consumption (1). In the present project, we aim to address these limitations by using the human nervous system itself as a model, which can process external information in a power-efficient way. To accomplish this objective, we utilize

Neural 3D organoids from human induced pluripotent stem cells (iPSC) are a rapidly developing technology with great potential for understanding brain development and neuronal diseases. A promising parallel approach is assembling structures similar to 3D spheroids or “neurospheres” by using defined combinations of fully differentiated human iPSC-derived cells in tri-culture, including glutamatergic neurons, GABAergic neurons, and astrocytes. In this study, we chose to model Alzheimer’s Disease (AD) by incorporating allelic variants of the ApoE gene (2/2, 3/4, and 4/4) to create disease-specific

Viral infection-induced inflammation during pregnancy has been associated to malformations of the fetal brain. Microglia, the brain-resident macrophages, respond to inflammatory signals and at the same time are actively involved in various aspects of brain development. We know surprisingly little about how microglia balance the different demands during human embryonic development and which functional consequences an inflammatory environment has on neuronal organization and connectivity. Human induced pluripotent stem cells (hiPSC) provide a unique opportunity to investigate this relationship.H

Neuronal networks derived from human induced pluripotent stem cells (hiPSCs) have gained attention for their potential use in in vitro modeling of epilepsy and seizure-like electrophysiological activity. Similar to in vivo animal models, seizure-like activity can be induced in these neuronal cultures using kainic acid (KA), direct agonist of the glutamate receptors. However, to establish more relevant in vitro model using KA, better understanding of KA mediated acute and prolonged effects on human neuronal networks is required. In this study, we investigated both acute and long-term KA concent

Schizophrenia (SCZ) is a debilitating psychiatric disorder, affecting approximately 1% of the global population. Estimates of the heritability rate of SCZ range around 80%, suggesting a strong genetic component. Loss-of-function mutations in SETD1A have been linked to both SCZ risk and other neurodevelopmental phenotypes. SETD1A is involved in chromatin remodeling through its function as a H3K4 methyltransferase, but how SETD1A loss-of-function mutations lead to altered brain function remains unclear. In the present study, we aim to gain insight into functional consequences of reduced SETD1A f

In vitro models of neuronal networks have proven to be a valuable tool for gaining deeper insights into the intricate mechanisms governing the human brain. Notably, the integration of human induced pluripotent stem cells (hiPSCs) with micro-electrode arrays (MEAs) provides a controlled in vitro environment to replicate and analyse both the structural and functional elements of the human brain. As neuronal communication relies on the emission of electrical (and chemical) stimuli, the employment of electrical stimulation becomes crucial for a comprehensive exploration of neuronal assemblies, to

Neuroinflammation represents a physiological response marked by immune cell activation and the release of inflammatory markers within the central nervous system. While it plays a pivotal protective role, when dysregulated it is also implicated in various neurological disorders such as Alzheimer disease. Brain organoids, self-organized three-dimensional (3D) aggregates derived from human induced pluripotent stem cells (iPSC), have emerged as a novel model to study brain development and disease. This study focuses on the development of a cerebral organoid model of neuroinflammation using pro and

The transcription factor P73 belongs to the p53 protein family, and its gene encodes two main isoforms: the transcriptionally active TAp73 isoform and the dominant-negative ΔNp73. Both isoforms play pivotal roles in regulating the self-renewal and differentiation of neural stem/progenitor cells, thus play a critical role in brain development during neuronal differentiation. Mutations in TP73 are associated with lissencephaly in humans and severe brain defects in mice. The role of TP73 and its isoforms during neurogenesis in human is still unclear. Aiming to further scrutinize the role of TAP73

HuD is an RNA-binding protein encoded by the ELAVL4 gene, which is expressed in the nervous system and plays a crucial role during nervous system development. However, recent evidence suggests its potential involvement in neurodegenerative processes, including Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease characterized by death of motoneurons (MNs). Notably, upregulation of both mRNA and protein levels of HuD has been observed in MNs derived from FUS P525L human induced pluripotent stem cells (hiPSCs) and in a Fus-Δ14 knock-in mouse model, impacting on MNs’ transcriptome and

In vitro models combined with human induced pluripotent stem cells (hiPSCs) are a widely used tool to investigate the complex mechanism of the human brain. Indeed, the use of hiPSCs-derived neuronal networks allow to create in vitro patient-specific models that most closely resembles the processes of the human system, providing a reliable model to test neuroactive properties of different compounds. This study investigates how different drugs affected the electrophysiological activity of in vitro systems composed by excitatory (E) and inhibitory (I) neurons derived from hiPSCs. Our experimental

Neurodevelopment is a finely orchestrated process marked by the sequential, but intimately connected events of synapse formation, maturation, and the critical GABA shift, where GABAergic neurotransmission transitions from excitatory to inhibitory. The precise timing and intricate balance of excitatory and inhibitory signaling is crucial for establishing functional neural circuits, and when disrupted contribute to neurodevelopmental disorders (NDDs) like autism spectrum disorder (ASD) and epilepsy. Exploring human aspects of neuronal development and functioning face challenges due to limitation

Tau, a microtubule-associated protein pivotal for neuronal integrity, is actively involved in retinal development, regulating growth, differentiation, and maturation processes. Mutations in tau can lead to misfolded protein and fibrils formation, disrupting cellular processes and damaging retinal tissue. Previous studies have identified pathological hallmarks of tauopathies, such as Frontotemporal Dementia (FTD), in the retina of patients even in the early stage of pathology. However, the precise molecular mechanisms and the direct sequence of events underlying this process remain poorly under

The mTOR pathway is a pivotal cellular signaling pathway that impacts neuronal differentiation and function. Genetic disruptions leading to hyperactivation of the mTOR pathway, termed mTORopathies, represent rare genetic and systemic disorders that are associated with altered brain development and epilepsy. However, the precise mechanisms by which disrupted mTOR signaling affects neuronal network development and signaling remain poorly understood. Human induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 genome editing, allowed the generation of a panel of isogenic iPSC lines carrying mutat