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HIGH-THROUGHPUT NEURAL CONNECTIVITY MAPPING IN ORGANOIDS REVEALS WIRING-DEFINED NEURONAL SUBTYPES AND ABERRANT WIRING IN TSC
Abel Vertesyand 8 co-authors
IMBA - Institute of Molecular Biotechnology Austria of OEAW
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS07-10AM-036
Presentation
Date TBA
Board: PS07-10AM-036
Event Information
Poster Board
PS07-10AM-036
Poster
View posterAbstract
The human brain is a complex network of ~80 billion neurons that changes with age, environment, and perturbations. To understand how and why these networks change, we need to integrate genetic perturbations, gene expression and connectivity data from individual cells, a gap current methods cannot bridge at scale.
We developed a 'connectomics-by-sequencing' method combining barcoded, rabies-based retrograde transsynaptic tracing with single-cell RNA sequencing. This approach allows mapping of thousands of synaptic networks and their transcriptomes simultaneously. To study both normal and pathological neural networks, we used IPS-based human cortical organoids, a scalable 3D disease model ideal for mapping connectivity.
Using this method, we identified connectivity patterns across different ages, cell lines, and disease conditions. We found that wiring of certain, but not all, cell types depend on tissue composition. We also demonstrated that upper layer excitatory neurons can be subtyped based on their connectivity, revealing differences in synapse organization genes.
In our Tuberous Sclerosis Complex (TSC) model, we identified disease-specific inversion of a network types (“motifs”) together with replacement of within upper layer cell states. These changes led to increasingly unspecific synaptic connections, a known hallmark of TSC.
Altogether, our method uncovered connectivity rules in healthy and diseased networks and linked altered connectivity to transcriptional state.
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