Electrophysiological characterization of heterogenous iPSC-derived neuronal networks

Electrophysiological methods are the gold standard to assess the function of neurons. At the Electrophysiology Facility (e-phac) we have recently established the use of High Density Microelectrode Array (HD-MEA) to assess the functional properties of IPSC-derived neurons at population level. Moreover, we have recently developed a correlative High Throughput Automated Patch Clamp (HT-APC) with high content screening to identify the recorded cells allowing us to functionally characterize heterogeneous populations at single cell level in very large numbers. To our knowledge, this novel technique is only available at e-phac. With this project, we aim to set up a collaboration between e-phac and Prof. Isaac Canals' group to characterize heterogeneous populations of neurons using high-throughput electrophysiological methods and correlative imaging.

We will leverage iPSC forward programming strategies towards excitatory (Zhang et al., 2013 Neuron) and inhibitory neurons (Yang et al., 2017 Nat Methods) as well as astrocytes (Canals et al., 2018 Nat Methods) to generate tricultures in similar proportions of those found in the human cortex. These protocols use overexpression of lineage specific transcription factors to promote differentiation of iPSCs towards pure populations of individual cell types. With this approach, we have the possibility to independently generate these three brain cell populations and mix them in different combinations of disease and healthy to examine the contribution of each cell type to a particular rare diseases. In this project, we will focus on Sanfilippo syndrome type C, a lysosomal storage disorder presenting with early-onset neurodegeneration.