Bidirectional Coupling between Astrocytes and Neurons Mediates Learning and Dynamic Coordination in the Brain: A Multiple Modeling Approach John J. Wade 1 *, Liam J. McDaid 1 , Jim Harkin 1 , Vincenzo Crunelli 2 , J. A. Scott Kelso 1,3 1 Intelligent Systems Research Centre, School of Computing and Intelligent Systems, University of Ulster, Derry, Northern Ireland, 2 Neuroscience Division, Cardiff School of Biosciences, University of Cardiff, Cardiff, United Kingdom, 3 Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, Florida, United States of America Abstract In recent years research suggests that astrocyte networks, in addition to nutrient and waste processing functions, regulate both structural and synaptic plasticity. To understand the biological mechanisms that underpin such plasticity requires the development of cell level models that capture the mutual interaction between astrocytes and neurons. This paper presents a detailed model of bidirectional signaling between astrocytes and neurons (the astrocyte-neuron model or AN model) which yields new insights into the computational role of astrocyte-neuronal coupling. From a set of modeling studies we demonstrate two significant findings. Firstly, that spatial signaling via astrocytes can relay a ‘‘learning signal’’ to remote synaptic sites. Results show that slow inward currents cause synchronized postsynaptic activity in remote neurons and subsequently allow Spike-Timing-Dependent Plasticity based learning to occur at the associated synapses. Secondly, that bidirectional communication between neurons and astrocytes underpins dynamic coordination between neuron clusters. Although our composite AN model is presently applied to simplified neural structures and limited to coordination between localized neurons, the principle (which embodies structural, functional and dynamic complexity), and the modeling strategy may be extended to coordination among remote neuron clusters. Citation: Wade JJ, McDaid LJ, Harkin J, Crunelli V, Kelso JAS (2011) Bidirectional Coupling between Astrocytes and Neurons Mediates Learning and Dynamic Coordination in the Brain: A Multiple Modeling Approach. PLoS ONE 6(12): e29445. doi:10.1371/journal.pone.0029445 Editor: Gennady Cymbalyuk, Georgia State University, United States of America Received September 23, 2011; Accepted November 28, 2011; Published December 29, 2011 Copyright: ß 2011 Wade et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Intelligent Systems Research Centre under the Centre of Excellence in Intelligent Systems grant, funded by the Integrated Development Fund and InvestNI. VC is supported by The Wellcome Trust (grant 91882), the MRC (900671) and the European Union (Health F2-2007- 202167). JASK is supported by NIMH grant 080838, NSF grant BCS0826897 and US ONR award N000140510117. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jj.wade@ulster.ac.uk Introduction For many years, astrocytes, a subgroup of glial cells found in the brain, have been thought to support neurons by providing them with vital elements needed for their survival [1–3]. In recent years, several new discoveries have revealed that astrocytes can encapsulate ,10 5 synapses and can connect to multiple neighboring neurons [4,5]. Although astrocytes cannot elicit propagating action potentials (APs) like neurons do, they can communicate in a bidirectional manner with neurons and other astrocytes by release of transmitters (which include glutamate and adenosine triphosphate (ATP) referred to as gliotransmitters) and propagating calcium (Ca 2+ ) waves. In particular, the interaction of glutamate with astrocytic receptors leads to transient elevation in astrocytic intracellular Ca 2+ levels [6–9], which represent a fundamental mode of excitation in astrocytes. In response to these Ca 2+ transients, astrocytes release gliotransmitters which in turn modulate synaptic transmission by acting both on pre- and post-synaptic receptors. As well as intracellular communication, astrocytes communicate with each other through the propagation of Ca 2+ waves, a process which is thought to be mediated via extracellular ATP diffusion and the transmission of inosotil 1, 4, 5-trisphosphate (IP 3 ) through gap junctions. However, the exact nature of this process is still unclear [10–14]. Traditionally, communication and information transfer within the brain have been the sole province of pre- and post-synaptic coupling between neurons. However, recent research has extended if not challenged this view of synaptic physiology. The coupling of astrocytes and neurons results in an intimate connection which provides a pathway for chemical communication between the cells: a synapse actually exchanges signals at three terminals, hence the name tripartite synapse [15]. Neuron to astrocyte communication is promoted by glutamate which is released across the synaptic cleft upon arrival of a presynaptic AP. Some of the released glutamate binds to metabotropic glutamate receptors (mGluRs) of the connected astrocyte resulting in an astrocytic intracellular release of IP 3 . This in turn regulates the release of Ca 2+ from internal stores, creating a transient increase in Ca 2+ (for a detailed review see [10,16]). Moreover, the intracellular Ca 2+ increase has also been shown to propagate intracellularly in a process which is believed to be promoted by the propagation of signaling proteins between neighboring microdomain clusters of IP 3 receptors [17,18]. Astrocytes also communicate in a feedback mode with neurons and have been found to play key roles in Long Term Potentiation/ PLoS ONE | www.plosone.org 1 December 2011 | Volume 6 | Issue 12 | e29445