Cl− homeodynamics in gap junction‐coupled astrocytic networks on activation of GABAergic synapses
Authors: Egawa Kiyoshi , Yamada Junko , Furukawa Tomonori , Yanagawa Yuchio , Fukuda Atsuo 
Published: June 2013

Key points

Astrocytes encapsulate GABAergic synapses and express GABAA receptors and GABA transporters. They are tightly coupled by gap junctions, and are referred to as the gap junction‐coupled astrocytic network.

With higher [Cl−]i, GABA application can mediate bidirectional Cl− fluxes in astrocytes, Cl− efflux via GABAA receptors, and Cl− influx along with GABA uptake via GABA transporters.

We focused on the Cl− dynamics of the astrocytic network under GABAergic synapse transmission. Spillover of GABA predominantly induced Cl− efflux via GABAA receptors, presumably because they are localized more closely to the synaptic cleft.

GABAA receptor‐mediated currents were propagated via gap junctions within the astrocytic network. These results indicate that Cl− efflux from astrocytes mediated by GABAergic transmission is homeostatically maintained within gap junction‐coupled astrocytic networks.

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−]o.

Abstract  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− flux has been hypothesized to affect the driving force for GABAergic transmission by modulating [Cl−]o. Thus, revealing the properties of GABA‐mediated astrocytic responses will deepen our understanding of GABAergic signal transmission. Here, we analysed the Cl− dynamics of neurons and astrocytes in CA1 hippocampal GABAergic tripartite synapses, using Cl− imaging during GABA application, and whole cell recordings from interneuron–astrocyte pairs in the stratum lacunosum‐moleculare. Astrocytic [Cl−]i was adjusted to physiological conditions (40 mm). Although GABA application evoked bidirectional Cl− flux via GABAA receptors and mouse GABA transporter 4 (mGAT4) in CA1 astrocytes, a train of interneuron firing induced only GABAA 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− efflux because GABAA receptors are localized near the synaptic clefts. This GABA‐induced Cl− efflux was accompanied by Cl− siphoning via the gap junctions of the astrocytic network because gap junction inhibitors significantly reduced the interneuron firing‐induced currents. Thus, Cl− 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− conductance within the astrocytic network may contribute to maintaining GABAergic synaptic transmission by regulating [Cl−]o.