Quantification of acute neurotoxic effects of trimethyltin using neuronal networks cultured on microelectrode arrays

We used spontaneously active monolayer networks in vitro, cultured on thin film microelectrode arrays as experimental platforms for the determination of trimethyltin chloride (TMT) toxicity. Two different tissues of the mouse CNS (spinal cord and auditory cortex) ex hibited characteristic and dose-dependent changes of their electrophysiolog ical activity patterns after treatment with TMT, a standard neurotoxicant. Spinal cord networks began to respond to TMT at 1-2 mu M and shut off activ ity at 4-7 mu M. Auditory cortex cultures started to respond at 2-3 mu M an d shut off activity at 7-8 mu M. Repeated applications of low doses of TMT always influenced the electrical activity in a reversible manner, with no o vert cytotoxic effects. The inhibitory concentrations for a 50% reduction o f activity (IC50) were 1.5 +/- 0.5 mu M (spinal cord) and 4.3 +/- 0.9 mu M (auditory cortex) indicating a relatively low interculture variability with in one tissue type. The non-overlapping IC50 range for cortical and spinal cord cultures may suggest tissue specificity for network responses to TMT. Shut-off concentrations were found to be within a factor of two of the leth al concentrations reported for mice in vivo. Action potential amplitude and shape did not change even when complete cessation of activity was approach ed, suggesting that acute TMT applications did not affect neuronal metaboli sm that would lead to a lowering of membrane potentials. Our results suggest that spontaneously active monolayer networks in vitro a re suitable for toxicological investigations since network activity can be influenced in a dose-dependent manner. These properties allow the developme nt of neurotoxicity biosensors based on physiological responses of spontane ously active networks. (C) 2000 Intox Press, Inc.