Abstract
Quantitatively benchmarking similarities and differences between the in vivo central nervous system and in vitro neuronal cultures can qualify discrepancies in functional responses and establish the utility of in vitro platforms. In this work, extracellular electrophysiology responses of cortical neurons in awake, freely-moving animals were compared to in vitro cultures of dissociated cortical neurons. After exposure to two well-characterized drugs, atropine and ketamine, a number of key points were observed: (1) significant differences in spontaneous firing activity for in vivo and in vitro systems, (2) similar response trends in single-unit spiking activity after exposure to atropine, and (3) greater sensitivity to the effects of ketamine in vitro. While in vitro cultures of dissociated cortical neurons may be appropriate for many types of pharmacological studies, we demonstrate that for some drugs, such as ketamine, this system may not fully capture the responses observed in vivo. Understanding the functionality associated with neuronal cultures will enhance the relevance of electrophysiology data sets and more accurately frame their conclusions. Comparing in vivo and in vitro rodent systems will provide the critical framework necessary for developing and interpreting in vitro systems using human cells that strive to more closely recapitulate human in vivo function and response.
Highlights
Efforts to develop human cell-based microphysiological systems that recapitulate organ function are aimed at reducing the extensive use of experimental animal models, which often inaccurately predict human specific responses[1,2]
Neuronal cultures are frequently used to evaluate the effects of drugs or toxicants on cellular responses, taking advantage of multi-electrode arrays (MEAs) to provide a means to non-invasively interrogate neuronal cell health and function[3,4,5,6,7]
Neuronal electrophysiology was compared between rodent cortical neurons cultured on planar MEAs and awake, freely moving rats using implantable MEA probes
Summary
Efforts to develop human cell-based microphysiological systems that recapitulate organ function are aimed at reducing the extensive use of experimental animal models, which often inaccurately predict human specific responses[1,2]. Responses to chemical stimuli between these systems is necessary Both experimental systems were exposed to two different drugs known to induce dual responses (i.e. both increases and decreases in single neuron firing rates): atropine and ketamine. These well-characterized drugs elicit effects both in vivo and in vitro and are known to work through interaction with different receptor populations involved in cortical function. Conducting direct comparisons between in vivo and in vitro experimental systems provides a more informed framework in which to interpret functional data and responses to chemical stimuli and has important implications for increasing the significance of drug development and toxicology studies. Our study illustrates that the relevance of results obtained from in vitro cultures likely depends on many factors including indirect neuronal effects that may be a result of neuroactive metabolites or the interaction of the parent compound with non-neuronal targets
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