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Open Access Highly Accessed Research article

Endogenous cholinergic tone modulates spontaneous network level neuronal activity in primary cortical cultures grown on multi-electrode arrays

Mark W Hammond1, Dimitris Xydas2, Julia H Downes2, Giovanna Bucci1, Victor Becerra2, Kevin Warwick2, Andrew Constanti3, Slawomir J Nasuto2 and Benjamin J Whalley1*

Author affiliations

1 School of Chemistry, Food and Nutritional Sciences and Pharmacy, University of Reading, Whiteknights, Reading, Berkshire, RG6 6AP, UK

2 School of Systems Engineering, University of Reading, Whiteknights, Reading, Berkshire, RG6 6AP, UK

3 UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK

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Citation and License

BMC Neuroscience 2013, 14:38  doi:10.1186/1471-2202-14-38

Published: 26 March 2013

Abstract

Background

Cortical cultures grown long-term on multi-electrode arrays (MEAs) are frequently and extensively used as models of cortical networks in studies of neuronal firing activity, neuropharmacology, toxicology and mechanisms underlying synaptic plasticity. However, in contrast to the predominantly asynchronous neuronal firing activity exhibited by intact cortex, electrophysiological activity of mature cortical cultures is dominated by spontaneous epileptiform-like global burst events which hinders their effective use in network-level studies, particularly for neurally-controlled animat (‘artificial animal’) applications. Thus, the identification of culture features that can be exploited to produce neuronal activity more representative of that seen in vivo could increase the utility and relevance of studies that employ these preparations. Acetylcholine has a recognised neuromodulatory role affecting excitability, rhythmicity, plasticity and information flow in vivo although its endogenous production by cortical cultures and subsequent functional influence upon neuronal excitability remains unknown.

Results

Consequently, using MEA electrophysiological recording supported by immunohistochemical and RT-qPCR methods, we demonstrate for the first time, the presence of intrinsic cholinergic neurons and significant, endogenous cholinergic tone in cortical cultures with a characterisation of the muscarinic and nicotinic components that underlie modulation of spontaneous neuronal activity. We found that tonic muscarinic ACh receptor (mAChR) activation affects global excitability and burst event regularity in a culture age-dependent manner whilst, in contrast, tonic nicotinic ACh receptor (nAChR) activation can modulate burst duration and the proportion of spikes occurring within bursts in a spatio-temporal fashion.

Conclusions

We suggest that the presence of significant endogenous cholinergic tone in cortical cultures and the comparability of its modulatory effects to those seen in intact brain tissues support emerging, exploitable commonalities between in vivo and in vitro preparations. We conclude that experimental manipulation of endogenous cholinergic tone could offer a novel opportunity to improve the use of cortical cultures for studies of network-level mechanisms in a manner that remains largely consistent with its functional role.

Keywords:
Acetylcholine; Endogenous cholinergic tone; Cortical culture; Multi-electrode array