Biology subjects

Fiskum, V.

Publications and source records attributed to Fiskum, V..

4 recordsLinked to original sources

bioRxiv2026

Structural and Synaptic Dysregulation Drives Network Vulnerability in APOE4 Human Neuronal Networks

Synaptic failure and associated neuronal network dysfunction are key pathological processes involved in the early stages of Alzheimers disease (AD). A better understanding of the specific synaptic pathways and network topologies that drive disease vulnerability is therefore essential for the development of a targeted therapeutic intervention. In the present study, we aimed to determine how defined synaptic pathways and connectivity patterns shape the emergence and progression of the structural and functional network dynamics of human neuronal networks with inherent vulnerability to AD. We performed longitudinal microelectrode array recordings, assessed excitatory and inhibitory activity, quantified neurite growth, and performed proteomic analyses of synaptosomes from human induced pluripotent stem cell-derived neuronal networks carrying homozygous apolipoprotein E epsilon 4 (APOE4), the strongest genetic risk factor for developing late-onset AD. This integrated approach enabled multiscale characterization of synaptic alterations, structural maturation, and functional network dynamics associated with AD vulnerability. Compared to isogenic homozygous APOE3 networks, we found that APOE4 drives a distinct topological regime, characterized by high assortativity combined with low transitivity, which reflects a compensatory organization with reduced redundancy and flexibility, consistent with an intrinsically fragile network structure. APOE4 networks exhibited reduced firing rates, dynamic excitatory and inhibitory imbalance, impaired synchronization, absence of network bursting, and reduced global routing efficiency. Despite retaining small-world properties indicative of baseline information processing capacity, the topological and functional profile of APOE4 networks suggests a reliance on compensatory mechanisms associated with elevated metabolic cost and increased susceptibility to pathological spread. Structurally, APOE4 networks displayed reduced dendritic length, branching, and total dendrite area, accompanied by dysregulation of synaptic organization and signaling, ion dynamics, and intracellular signaling pathways. Together, these findings establish that APOE4 drives a multiscale reorganization of neuronal networks that not only mirrors synaptic alterations identified in patients, but also contextualizes these changes within network-level dynamics, advancing a more comprehensive understanding of early AD pathology.

neuroscience↗

bioRxiv2025

Microscale dysfunction and mesoscale compensation in degenerating neuronal networks

Progressive neurodegenerative diseases involve neuronal dysfunction from cellular to circuit to whole-brain levels, but complexity and variability, both between and within diseases, pose significant research challenges. However, although they are differentiated by anatomical origins, vulnerable neuronal subtypes, and specific misfolded proteins, neurodegenerative diseases also share many important features. During presymptomatic disease phases, neural networks initiate multiple compensatory processes to maintain network function, including increased network centralisation and reliance on a rich-club of hub nodes, which have been proposed as common reconfigurations to neural network damage. Currently, while supporting evidence for such mechanisms has been found in some neurodegenerative diseases, it is limited in others, like ALS. This knowledge gap makes it challenging to ascertain if there are indeed common pre-symptomatic mechanisms within and across different neurodegenerative diseases. To address this, we investigated the structural and functional properties of ALS patient derived motor neuron networks and counterpart networks from a healthy donor using longitudinal multielectrode array recordings and graph theory-based network analysis. We demonstrate microscale-level motor neuron dysfunction, including TDP-43 proteinopathy, hyperactivity and reduced spike amplitude. Structurally, we observed neurite hypertrophy, indicating that degenerating networks attempt to establish new connections. We furthermore document mesoscale-level functional reconfigurations, including increased rich-club connectivity and network assortativity, indicating functional compensation in ALS where networks become more centralised to maintain computational capacity. We thus provide novel evidence that ALS networks become increasingly centralised, which places progressively mounting demands on a rich-club, predisposing networks to further damage, consistent with existing models of common reconfigurations in neurodegenerative disease. Significance statementThis study makes significant contributions to preclinical modelling of neurodegenerative disease, with specific relevance for ALS research. By utilising human cellular models, longitudinal extracellular electrophysiology, and advanced network analysis, we show that known features of ALS can be recapitulated in in vitro engineered neural networks, and that these networks allow for novel hypothesis testing and identification of pre-symptomatic pathological processes including increased centralisation. This has previously been observed in other neurodegenerative diseases, but evidence has been limited in ALS. Our results advance our understanding of motor neuron network dynamics in ALS and contribute to a shared understanding of how neurodegenerative diseases affect neural networks which go beyond specific disease diagnosis, elucidating fundamental processes in neural network function and disease response.

neuroscience↗

bioRxiv2024

ALS patient-derived motor neuron networks exhibit microscale dysfunction and mesoscale compensation rendering them highly vulnerable to perturbation

Amyotrophic lateral sclerosis affects upper and lower motor neurons, causing progressive neuropathology leading to structural and functional alterations of affected neural networks long prior to development of symptoms. Certain genetic mutations, such as expansions in C9orf72, predispose motor neuron populations to pathological dysfunction. However, it is not known how underlying pathological predisposition affects structural and functional dynamics within vulnerable networks. Here, we studied micro-and mesoscale dynamics of ALS patient derived motor neuron networks over time. We show, for the first time, that ALS patient derived motor neurons with endogenous genetic predisposition develop classical ALS cytopathology in the form of cytoplasmic TDP-43 inclusions and self-organise into computationally efficient networks, albeit with functional hallmarks of higher metabolic cost compared to healthy controls. These hallmarks included microscale impairments and mesoscale compensation including increased centralisation of function. Moreover, we show that these networks are highly susceptible to transient perturbation by exhibiting induced hyperactivity.

neuroscience↗

bioRxiv2019

Modelling functional human neuromuscular junctions in a differentially-perturbable microfluidic environment, validated through recombinant monosynaptic pseudotyped ΔG-rabies virus tracing

Compartmentalized microfluidic culture systems provide new perspectives in in vitro disease modelling as they enable co-culture of different relevant cell types in interconnected but fluidically isolated microenvironments. Such systems are thus particularly interesting in the context of in vitro modelling of mechanistic aspects of neurodegenerative diseases such as amyotrophic lateral sclerosis, which progressively affect the function of neuromuscular junctions, as they enable the co-culture of motor neurons and muscle cells in separate, but interconnected compartments. In combination with cell reprogramming technologies for the generation of human (including patient-specific) motor neurons, microfluidic platforms can thus become important research tools in preclinical studies. In this study, we present the application of a microfluidic chip with a differentially-perturbable microenvironment as a platform for establishing functional neuromuscular junctions using human induced pluripotent stem cell derived motor neurons and human myotubes. As a novel approach, we demonstrate the functionality of the platform using a designer pseudotyped {Delta}G-rabies virus for retrograde monosynaptic tracing.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC=\"FIGDIR/small/745513v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (91K):\norg.highwire.dtl.DTLVardef@d34487org.highwire.dtl.DTLVardef@3804b8org.highwire.dtl.DTLVardef@1be0389org.highwire.dtl.DTLVardef@1da414c_HPS_FORMAT_FIGEXP M_FIG Functional neuromuscular junction in a microfluidic chip\n\n(a) Overview of microfluidic chip. Human iPS cell-derived motor neuron aggregates (spheroids indicated by black arrows) are seeded in the three lateral compartments of the chip, while human myotubes (white arrows) are seeded in the middle compartment.\n\n(b) Directed connectivity and retrograde virus tracing. Outgrowing axons (yellow arrow) from the motor neuron aggregate enter the directional axon tunnels (grey rectangles) and form connections with the myotubes (white arrow) within the opposite compartment. Addition of a designer monosynaptic pseudotyped {Delta}G-rabies virus to the myotube compartment, infects the myotubes (green) expressing an exogenous receptor (TVA) and rabies glycoprotein (G), subsequently making infectious viruses that are retrogradely transported through the motor neuron axons (green arrow) back to the neuronal cell bodies within the aggregate, validating neuromuscular junction functionality.\n\nC_FIG

neuroscience↗