Human Pluripotent Stem Cell-Derived Neuronal Networks:Their Electrical Functionality and Usability for Modelling and Toxicology

Abstract

Micro electrode array (MEA)-based platforms have been used to study neuronal networks for decades. The used cells have, for the most part, been rodent primary neurons. The gained knowledge has indeed increased the understanding of neuronal network development and maturation both in vitro and in vivo. If aiming to understand the development of human brain, however, the used cell type should preferably be of human origin due to difficult interpolation from the rodent cell data. In addition, the development of functional human neuronal networks would open up a new era for, e.g., toxicology testing, drug screening and disease modelling. The use of MEA with bioelectrically active cells was first reported by Thomas et al. 1972. Gross et al. (1977; 1979) extended the applicability of the MEA platform to long-term recordings of neuronal cells and Pine (1980) reported the first recordings from dissociated neurons. Interestingly, although the solutions related to the MEA fabrication and design were similar in the above mentioned papers, all three groups came to their conclusions independently demonstrating the drive and need to record neurons in vitro. MEAs have been successfully tested in several species and cell types using organotypic and primary dissociated cell cultures. Due to their ease of use, the long-term survival of the cultures and vast possibilities of manipulation of the culture, MEAs provide an attractive tool to explore basic neuroscience as well as for pharmacology and toxicology. Functional neuronal networks have been derived from mouse embryonic stem cells (Evans & Kaufman 1981; Martin 1981), but the invention of culturing human embryonic stem cells (Thomson et al., 1998) and human induced pluripotent stem cells (Takahashi et al., 2007) have enabled the researchers to build up human cell-derived neuronal cells and networks (Ban et al., 2006; Carpenter et al., 2001; Heikkila et al., 2009; Karumbayaram et al., 2009; Nat et al., 2007). These studies have proved that human pluripotent stem cell-derived neuronal cells are indeed capable of forming functional neuronal networks which most likely resemble the networks in human brain. These human-derived neuronal networks have increased and will further increase the understanding of human brain development and functions. More importantly, with these networks it is possible to model the “normal” brain