Activity and High-Order Effective Connectivity Alterations in Sanfilippo C Patient-Specific Neuronal Networks

Induced pluripotent stem cell (iPSC) technology has been successfully used to recapitulate phenotypic traits of several human diseases in vitro. Patient-specific iPSC-based disease models are also expected to reveal early functional phenotypes, although this remains to be proved. Here, we generated iPSC lines from two patients with Sanfilippo type C syndrome, a lysosomal storage disorder with inheritable progressive neurodegeneration. Mature neurons obtained from patient-specific iPSC lines recapitulated the main known phenotypes of the disease, not present in genetically corrected patient-specific iPSC-derived cultures. Moreover, neuronal networks organized in vitro from mature patient-derived neurons showed early defects in neuronal activity, network-wide degradation, and altered effective connectivity. Our findings establish the importance of iPSC-based technology to identify early functional phenotypes, which can in turn shed light on the pathological mechanisms occurring in Sanfilippo syndrome. This technology also has the potential to provide valuable readouts to screen compounds, which can prevent the onset of neurodegeneration. [Display omitted] •Fibroblasts from two Sanfilippo C patients were reprogrammed to obtain iPSCs•iPSCs were successfully differentiated to neural cells that mimic the disease•Networks of patients’ neurons show altered activity and connectivity•Early functional phenotypes are prevented in gene-corrected patients’ neurons iPSC technology has been used to model dozens of diseases. In this article, Raya, Grinberg, and colleagues take a step forward and show that this technology can also be used to model pre-symptomatic stages of human diseases. In particular, they used it to generate neurons from Sanfilippo C patients and found functional alterations in how these neurons interacted with one another, before the neurons themselves had any obvious alteration.