Project ID NS-MH2024_55


Co Supervisor 1A Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

Co Supervisor 1B Institute of Psychiatry, Psychology & Neuroscience, School of Neuroscience, Department of Basic & Clinical NeuroscienceWebsite

A bioengineered human model of neuronal connectivity to better understand synapses

Background: Synapse formation and maturation is arguably one of the most important steps to ensure the function of neural circuits during development. At the same time, synaptic defects and loss of synaptic functionality are common features across many neurodegenerative diseases. While modelling human neurons in vitro has been an invaluable tool for some time, studying single neurons in random arrangements does not allow to properly investigate the links between circuit architecture, connectivity and the molecular changes in synaptic machinery that occur at different stages of development, but also during the onset of neurodegeneration.

Our teams have recently developed a bioengineered platform that allows to generate complex large format neuronal circuity with controlled architecture, which can be used for live imaging studies but also can be disassembled in their constituent components to perform molecular studies (e.g. RNAseq/proteomics across different regions of the circuit). The aim of this project is to use this humanised model platform, together with live imaging reporters for synaptic activity and neuronal function, as well as engineered human stem cell lines, to characterise the links between circuit complexity and synaptic maturation.

Rotation Project:
During the rotation project we will optimise the protocols for assembly of complex neuronal circuitry with defined architecture using human stem cell derived cortical neurons, to obtain reliably different circuit arrangements (e.g. 2 nodes, 3 nodes, etc) and characterise the timeline of synaptic development by immunostaining across different timepoints

PhD Project:
During the PhD we will use the established protocols to first compare the timeline of synaptic establishment and maturation across different circuit architecture in vitro (Y1), then perform molecular analysis at the RNA and protein level by separating different compartment of the circuits across timepoints (Y2), and finally we will use this system to study synaptopathies mechanisms in neurodegenerative disorders (Y3).

Skills & Training: the student will work in an interdisciplinary team, learning different skills across neurobiology, stem cell differentiation, live imaging, electrophysiology, bioengineering, microfabrication and developmental biology.

Representative Publications

Hagemann, C. et al. Axonal Length Determines Distinct Homeostatic Phenotypes in Human iPSC Derived Motor Neurons on a Bioengineered Platform. Adv Healthc Mater 2101817 (2022) doi:10.1002/adhm.202101817.

Hagemann, C. et al. Combining SLA 3D printing and soft lithography for fast, versatile, and accessible high-resolution fabrication of customised multiscale cell culture devices with complex designs. Biorxiv 2022.02.22.481424 (2022) doi:10.1101/2022.02.22.481424.

Harley, J., Hagemann, C., Serio, A. & Patani, R. FUS is lost from nuclei and gained in neurites of motor neurons in a human stem cell model of VCP-related ALS. Brain 143, awaa339 (2020).

Martínez-Serra R., Alonso-Nanclares L., Cho K. & Giese P. (2022) Emerging insights into synapse dysregulation in Alzheimer’s disease. Brain Comms 4, 2022, fcac083.

Regan P., Mitchell S.J., Kim S-C., Lee Y., Yi J.H., Barbati S.A., Shaw C. & Cho K. (2021) Regulation of synapse weakening through interactions of the microtubule associated protein tau with PACSIN1. J Neurosci 41, 7162-7170.

Hughes C., Choi M.L., Yi J-H, Kim S-C, Drews A., St George-Hyslop P., Bryant C., Gandhi S., Cho K. & Klenerman D. (2020) A? aggregates induce sensitised TLR4 signalling causing LTP deficit and neuronal cell death. Commun Biol. 3:79.