Applications of multi-electrode array system in drug discovery using acute and cultured hippocampal slices

Abstract

There are currently only limited technologies for discovering, classifying, and testing compounds that could significantly affect cognitive performance in humans. This chapter describes ways in which multi-electrode arrays can successfully be used in this context. The proposed approach emerged from collaborations between research groups at the University of California, Irvine (UCI), the University of Southern California (USC), and Tensor Biosciences. The academic groups have, for a number of years, been developing protocols and analytical software for activating and analyzing electrophysiological responses generated by complex networks in mammalian CNS. This approach represents an effort to record the nearly second-long events that are possibly the substrate of simple cognitive actions; it can also be seen as an attempt to create an experimental platform for practical applications of neural network research. Tensor Biosciences is a startup company that was founded by researchers at UCI and USC and is pursuing a multiyear contract with Matsushita Electric Industrial Co., Ltd. (Panasonic) to develop software for Panasonics multi-electrode array system (MED64 System) and also build drug discovery platforms by using the MED64 System. Panasonic and its subsidiary, Alpha MED Sciences, have been gradually evolving turnkey hardware and software for stimulating and recording from 64 electrodes placed beneath a brain slice. Biologically or chemically induced changes in network behavior are ultimately a reflection of effects on synaptic and extrasynaptic activity in brain networks. The latter are not easily predicted by the agents physiological actions at the molecular and cellular levels. Rather, networks are premier examples of complex systems in which small changes in initial conditions can have large and unexpected consequences. It seems reasonable to assume that actions of psychoactive agents at the network level are substantially larger in magnitude than their actions on individual synapses. This point has been experimentally confirmed for ampakines, a class of compounds that positively modulate AMPA-type glutamate receptors. For instance, ampakine-induced changes on the hippocampal trisynaptic loop were severalfold greater in magnitude than changes in monosynaptic responses within this circuit (Sirvio et al., 1996). Moreover, compound concentrations necessary to enhance polysynaptic potentials proved to be about four times smaller than those required to increase monosynaptic field EPSPs (Sirvio et al., 1996). In addition, ascending modulatory systems such as the cholinergic or the monoaminergic systems widely influence cortical network activity. In in vitro preparations, actions of modulatory systems on cortical networks can be mimicked by pharmacological compounds acting pre- or postsynaptically in the target areas of these neuromodulatory systems. We address this issue in this chapter, thereby emphasizing multi-electrode arrays as an important tool to identify and evaluate novel neuropharmacological compounds.