Altered network communication following a neuroprotective drug treatment

PLoS One. 2013;8(1):e54478. doi: 10.1371/journal.pone.0054478. Epub 2013 Jan 22.


Preconditioning is defined as a range of stimuli that allow cells to withstand subsequent anaerobic and other deleterious conditions. While cell protection under preconditioning is well established, this paper investigates the influence of neuroprotective preconditioning drugs, 4-aminopyridine and bicuculline (4-AP/bic), on synaptic communication across a broad network of in vitro rat cortical neurons. Using a permutation test, we evaluated cross-correlations of extracellular spiking activity across all pairs of recording electrodes on a 64-channel multielectrode array. The resulting functional connectivity maps were analyzed in terms of their graph-theoretic properties. A small-world effect was found, characterized by a functional network with high clustering coefficient and short average path length. Twenty-four hours after exposure to 4-AP/bic, small-world properties were comparable to control cultures that were not treated with the drug. Four hours following drug washout, however, the density of functional connections increased, while path length decreased and clustering coefficient increased. These alterations in functional connectivity were maintained at four days post-washout, suggesting that 4-AP/bic preconditioning leads to long-term effects on functional networks of cortical neurons. Because of their influence on communication efficiency in neuronal networks, alterations in small-world properties hold implications for information processing in brain systems. The observed relationship between density, path length, and clustering coefficient is captured by a phenomenological model where connections are added randomly within a spatially-embedded network. Taken together, results provide information regarding functional consequences of drug therapies that are overlooked in traditional viability studies and present the first investigation of functional networks under neuroprotective preconditioning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / administration & dosage*
  • Animals
  • Bicuculline / administration & dosage*
  • Brain / drug effects*
  • Brain / physiopathology
  • Brain Mapping
  • Electroencephalography
  • Nerve Net* / drug effects
  • Nerve Net* / physiopathology
  • Neural Pathways* / drug effects
  • Neural Pathways* / physiology
  • Neural Pathways* / physiopathology
  • Neurons / drug effects
  • Neurons / physiology
  • Neuroprotective Agents / administration & dosage
  • Rats


  • Neuroprotective Agents
  • 4-Aminopyridine
  • Bicuculline

Grant support

This research was supported by a grant to J.P.T. from the NAKFI Keck Future Initiatives and intramural funding from the National Research Council Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.