Cl− homeodynamics in gap junction‐coupled astrocytic networks on activation of GABAergic synapses. (8th July 2013)

• Record Type: Journal Article
• Authors: Egawa, Kiyoshi; Yamada, Junko; Furukawa, Tomonori; Yanagawa, Yuchio; Fukuda, Atsuo
• Is Part Of: Journal of physiology. Volume 591:Number 16(2013:Aug.)
• Page Start: 3901
• Page End: 3917
• Publication Date: 2013-07-08
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2013.257162
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Key points</title> <p> <list id="l1" list-type="simple"> <list-item> <label> </label> <p>Astrocytes encapsulate GABAergic synapses and express GABA<sub>A</sub> receptors and GABA transporters. They are tightly coupled by gap junctions, and are referred to as the gap junction‐coupled astrocytic network.</p> </list-item> <list-item> <label> </label> <p>With higher [Cl<sup>−</sup>]<sub>i, </sub> GABA application can mediate bidirectional Cl<sup>−</sup> fluxes in astrocytes, Cl<sup>−</sup> efflux via GABA<sub>A</sub> receptors, and Cl<sup>−</sup> influx along with GABA uptake via GABA transporters.</p> </list-item> <list-item> <label> </label> <p>We focused on the Cl<sup>−</sup> dynamics of the astrocytic network under GABAergic synapse transmission. Spillover of GABA predominantly induced Cl<sup>−</sup> efflux via GABA<sub>A</sub> receptors, presumably because they are localized more closely to the synaptic cleft.</p> </list-item> <list-item> <label> </label> <p>GABA<sub>A</sub> receptor‐mediated currents were propagated via gap junctions within the astrocytic network. These results indicate that Cl<sup>−</sup> efflux from astrocytes mediated by GABAergic transmission is homeostatically maintained within gap junction‐coupled astrocytic networks.</p> </list-item> <list-item> <label> </label> <p>Blockage of gap junctional coupling by octanol promoted the collapse of the driving force for neuronal inhibitory transmission during intense activation of GABAergic synapses. Thus, the astrocytic network may play a role in maintaining GABAergic transmission by regulating [Cl<sup>−</sup>]<sub>o</sub>.</p> </list-item> </list> </p> <p> <bold>Abstract </bold> The electrophysiological properties and functional role of GABAergic signal transmission from neurons to the gap junction‐coupled astrocytic network are still unclear. GABA‐induced astrocytic Cl<sup>−</sup> flux has been hypothesized to affect the driving force for GABAergic transmission by modulating [Cl<sup>−</sup>]<sub>o</sub>. Thus, revealing the properties of GABA‐mediated astrocytic responses will deepen our understanding of GABAergic signal transmission. Here, we analysed the Cl<sup>−</sup> dynamics of neurons and astrocytes in CA1 hippocampal GABAergic tripartite synapses, using Cl<sup>−</sup> imaging during GABA application, and whole cell recordings from interneuron–astrocyte pairs in the stratum lacunosum‐moleculare. Astrocytic [Cl<sup>−</sup>]<sub>i</sub> was adjusted to physiological conditions (40 m<sc>m</sc>). Although GABA application evoked bidirectional Cl<sup>−</sup> flux via GABA<sub>A</sub> receptors and mouse GABA transporter 4 (mGAT4) in CA1 astrocytes, a train of interneuron firing induced only GABA<sub>A</sub> receptor‐mediated inward currents in an adjacent astrocyte. A GAT1 inhibitor increased the interneuron firing‐induced currents and induced bicuculline‐insensitive, mGAT4 inhibitor‐sensitive currents, suggesting that synaptic spillover of GABA predominantly induced the astrocytic Cl<sup>−</sup> efflux because GABA<sub>A</sub> receptors are localized near the synaptic clefts. This GABA‐induced Cl<sup>−</sup> efflux was accompanied by Cl<sup>−</sup> siphoning via the gap junctions of the astrocytic network because gap junction inhibitors significantly reduced the interneuron firing‐induced currents. Thus, Cl<sup>−</sup> efflux from astrocytes is homeostatically maintained within astrocytic networks. A gap junction inhibitor enhanced the activity‐dependent depolarizing shifts of reversal potential of neuronal IPSCs evoked by repetitive stimulation to GABAergic synapses. These results suggest that Cl<sup>−</sup> conductance within the astrocytic network may contribute to maintaining GABAergic synaptic transmission by regulating [Cl<sup>−</sup>]<sub>o</sub>.</p> </abstract>