High throughput microelectrode array platforms for quantitative pharmacology, toxicology, and drug development using spontaneously active neural tissue

Abstract

Primary cell cultures, derived from dissociated murine central nervous system tissue, form stable, spontaneously active networks on microelectrode arrays (MEAs) that provide long-term action potential readout from many discriminated units and simultaneous optical information on cell condition and general network morphology. The spontaneous activity is driven by competing ignition sites (burst leaders) that form a primary, monosynaptically connected circuit (1). Such cell group activity represents a window to the internal dynamics of self-organized networks, but also provides reproducibility and fault tolerance through the use of ensemble activity. In addition to supporting theoretical studies, it is now clear that these networks can be used in pharmacology, toxicology, and as tissue-based biosensors. Experimental evidence shows such models to be "histiotypic", as their responses are highly similar to those of the parent tissue in vivo. The networks, which consist of nonneuronal glia cells as well as brain region-specific different neuronal subtypes, reliably report a range of toxic responses: cytotoxicity (death of all cells), neurotoxicity (death of subtypes of neurons), and functional toxicity (loss of electrical function in the absence of cell death). Reproducible dose response curves for many compounds have been obtained (2) and dissociation constants for bicuculline, gabazine, and trimethylolpropanephosphate have been calculated from network activity changes (3). However, before such systems can be used effectively for rapid toxicity screening or for drug development, it is essential to develop high throughput platforms. © 2009 Springer-Verlag.