Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons DOI

Anna M. Kollstrøm,

Nicholas Christiansen, Axel Sandvig

и другие.

AJP Cell Physiology, Год журнала: 2024, Номер 328(3), С. C1029 - C1044

Опубликована: Дек. 27, 2024

Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper lower motor neurons. Several studies have identified structural functional alterations in the neurons before manifestation symptoms, yet underlying cause such how they contribute to progressive degeneration affected neuron networks remain unclear. Importantly, short- long-term spatiotemporal dynamics neuronal network activity make it challenging discern ALS-related reconfigurations emerge evolve. To address this, we systematically monitored with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived display time-dependent neural dysfunction, specifically reduced firing rate spike amplitude, impaired bursting, but higher overall synchrony activity. These changes coincided altered neurite outgrowth branching within networks. Moreover, transcriptional analyses revealed dysregulation molecular pathways involved synaptic development maintenance, outgrowth, cell adhesion, suggesting stabilization. This study identifies early as contributing mechanism resulting network-wide compensation, which may over time render vulnerable neurodegeneration.NEW & NOTEWORTHY RNA-sequencing expression genes plasticity. were accompanied impairments disrupted activity, compensations vulnerability ALS.

Язык: Английский

Micro-and mesoscale aspects of neurodegeneration in engineered human neural networks carrying the LRRK2 G2019S mutation DOI Creative Commons
Vibeke Devold Valderhaug, Ola Huse Ramstad, Rosanne van de Wijdeven

и другие.

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Апрель 5, 2024

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been widely linked to Parkinson’s disease, where G2019S variant has shown contribute uniquely both familial and sporadic forms of disease. LRRK2-related mutations extensively studied, yet wide variety cellular network events related these remain poorly understood. The advancement availability tools for neural engineering now enable modeling selected pathological aspects neurodegenerative disease human networks vitro . Our study revealed distinct pathology associated dynamics engineered cortical carrying LRRK2 mutation compared healthy isogenic control networks. neurons self-organized into with aberrant morphology mitochondrial dynamics, affecting emerging structure–function relationships at micro-and mesoscale. Taken together, findings our points toward an overall heightened metabolic demand mutation, as well a resilience change response perturbation, controls.

Язык: Английский

Процитировано

7
Engineered Cortical Microcircuits for Investigations of Neuroplasticity DOI
Nicolai Winter‐Hjelm, Pawel Sikorski, Axel Sandvig

и другие.

Lab on a Chip, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

An advanced microfluidic platform integrated with a microelectrode array for the study of structural and functional adaptations neural networks in response to localized perturbations.

Язык: Английский

Процитировано

2
Reverse engineering of feedforward cortical-Hippocampal microcircuits for modelling neural network function and dysfunction DOI Creative Commons
Katrine Sjaastad Hanssen, Nicolai Winter‐Hjelm,

Salome Nora Niethammer

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Окт. 29, 2024

Abstract Engineered biological neural networks are indispensable models for investigation of function and dysfunction from the subcellular to network level. Notably, advanced neuroengineering approaches significant interest their potential replicate topological functional organization brain networks. In this study, we reverse engineered feedforward primary cortical hippocampal neurons, using a custom-designed multinodal microfluidic device with Tesla valve inspired microtunnels. By interfacing nanoporous microelectrodes, show that exhibit capacity both segregated integrated activity, mimicking dynamics. To advocate broader applicability our model system, induced localized perturbations amyloid beta study impact pathology on functionality. Additionally, demonstrate long-term culturing subregion- layer specific neurons extracted entorhinal cortex hippocampus adult Alzheimer’s-model mice rats. Our results thus highlight approach engineering anatomically relevant dynamic structure-function relationships in healthy pathological conditions.

Язык: Английский

Процитировано

2
Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons DOI Creative Commons

Anna M. Kollstrøm,

Nicholas Christiansen, Axel Sandvig

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 31, 2024

Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper lower motor neurons. Several studies have identified structural functional alterations in the neurons before manifestation symptoms, yet underlying cause such how they contribute to progressive degeneration affected neuron networks remain unclear. Importantly, short long-term spatiotemporal dynamics neuronal network activity make it challenging discern ALS-related reconfigurations emerge evolve. To address this, we systematically monitored with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived display time-dependent neural dysfunction, specifically reduced firing rate spike amplitude, impaired bursting, but higher overall synchrony activity. These changes coincided altered neurite outgrowth branching within networks. Moreover, transcriptional analyses revealed dysregulation molecular pathways involved synaptic development maintenance, cell adhesion, suggesting stabilization. This study identifies early as contributing mechanism resulting network-wide compensation, which may over time render vulnerable neurodegeneration.

Язык: Английский

Процитировано

1
Engineered Cortical Microcircuits for Investigations of Neuroplasticity DOI Creative Commons
Nicolai Winter‐Hjelm, Pawel Sikorski, Axel Sandvig

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 8, 2024

Abstract Recent advances in neural engineering have opened new ways to investigate the impact of topology on network function. Leveraging microfluidic technologies, it is possible establish modular circuit motifs that promote both segregation and integration information processing engineered networks, similar those observed vivo . However, underlying topologies dynamics response pathological perturbation remains largely unresolved. In this work, we demonstrate utilization platforms with 12 interconnected nodes structure modular, cortical networks. By implementing geometrical constraints inspired by a Tesla valve within connecting microtunnels, additionally exert control over direction axonal outgrowth between nodes. Interfacing these nanoporous microelectrode arrays reveals resulting laminar networks exhibit pronounced segregated integrated functional across layers, mirroring key elements feedforward, hierarchical neocortex. The multi-nodal configuration also facilitates selective individual To illustrate this, induced hypoxia, factor pathogenesis various neurological disorders, well-connected Our findings such perturbations induce ablation flow hypoxic node, while enabling study plasticity adaptations neighboring communication pathways. summary, our presented model system recapitulates fundamental attributes microcircuit organization neocortical rendering highly pertinent for preclinical neuroscience research. This holds promise yielding insights into development, topological organization, neuroplasticity mechanisms neocortex micro- mesoscale level, healthy conditions.

Язык: Английский

Процитировано

0
Dysregulation of synaptic transcripts underlies network abnormalities in ALS patient-derived motor neurons DOI

Anna M. Kollstrøm,

Nicholas Christiansen, Axel Sandvig

и другие.

AJP Cell Physiology, Год журнала: 2024, Номер 328(3), С. C1029 - C1044

Опубликована: Дек. 27, 2024

Amyotrophic lateral sclerosis (ALS) is characterized by dysfunction and loss of upper lower motor neurons. Several studies have identified structural functional alterations in the neurons before manifestation symptoms, yet underlying cause such how they contribute to progressive degeneration affected neuron networks remain unclear. Importantly, short- long-term spatiotemporal dynamics neuronal network activity make it challenging discern ALS-related reconfigurations emerge evolve. To address this, we systematically monitored with a confirmed endogenous C9orf72 mutation. We show that ALS patient-derived display time-dependent neural dysfunction, specifically reduced firing rate spike amplitude, impaired bursting, but higher overall synchrony activity. These changes coincided altered neurite outgrowth branching within networks. Moreover, transcriptional analyses revealed dysregulation molecular pathways involved synaptic development maintenance, outgrowth, cell adhesion, suggesting stabilization. This study identifies early as contributing mechanism resulting network-wide compensation, which may over time render vulnerable neurodegeneration.NEW & NOTEWORTHY RNA-sequencing expression genes plasticity. were accompanied impairments disrupted activity, compensations vulnerability ALS.

Язык: Английский

Процитировано

0