Expanding the Dynamic Range of Light Microscopy-Based Analysis of Physiological and Aberrant Neural Circuit Development (EXPAND)

AdaBD made easy

Research project

The project EXPAND combines Expansion Microscopy (ExM), a method that expands biological samples up to 20 times, with other super-resolution microscopy approaches to investigate chemical synapses and neural circuits at the nanometer scale. Moreover, we image neural circuits  in large samples with increased resolution by combining ExM with mesoscale selective plane illumination microscopy (mesoSPIM). This allows us to bridge the gap between the subsynaptic and the neural circuit level and to elucidate how gene variants causing neurodevelopmental disorders affect neural circuit architecture across spatial scales.

So far, we have investigated several genes (CADPS, FoxP1, FoxP2, and FoxP4) associated with neurodevelopmental disorders. Our results contribute to a better understanding of the roles of these de novo variants in neural disorders. For instance, our experiments revealed that loss of function of a synaptic gene (CADPS) enhances neuronal excitability, which may relate to the epilepsy phenotype of the patients. We also revealed specific defects in axon guidance in the peripheral nervous system after knocking down FoxP1, FoxP2, and FoxP4. The identified phenotypes after loss of FoxP1, FoxP2, and FoxP4 are in line with a potential contribution to the sensory perception differences seen in ASD patients

We have established several ExM protocols and integrated them with super-resolution light microscopy techniques, across different experimental systems, including the Drosophila neuromuscular junction (NMJ), chicken cerebellum, and human iPSC-derived neuronal cultures. Furthermore, we have begun combining ExM with stimulated emission depletion (STED) super-resolution microscopy to investigate the homeostatic modulation of synaptic nano-architecture in human iPSC-derived neurons and Drosophila synapses. Thus, this project provides the URPP with a versatile toolbox and an experimental pipeline that allows the systematic examination of neural circuits at increased resolution, and the characterization of candidate disease genes identified in patients.

Research groups

Principal investigators: Martin Müller, Esther Stoeckli, Anita Rauch

PhD students: Nasrin Bollmohr, Marta Brasili, Hanna Yeliseyeva

Collaborators: Gonzalo Saiz-Castro, Gabriele Siegel, Severino Thomasin, Lisa Kistler

Platforms: mesoSPIM