Gap junction coupling confers isopotentiality on astrocyte syncytium

Abstract

Astrocytes are extensively coupled through gap junctions into a syncytium. However, the basic role of this major brain network remains largely unknown. Using electrophysiological and computational modeling methods, we demonstrate that the membrane potential (VM) of an individual astrocyte in a hippocampal syncytium, but not in a single, freshly isolated cell preparation, can be well-maintained at quasi-physiological levels when recorded with reduced or K+ free pipette solutions that alter the K+ equilibrium potential to non-physiological voltages. We show that an astrocyte’s associated syncytium provides powerful electrical coupling, together with ionic coupling at a lesser extent, that equalizes the astrocyte’s VM to levels comparable to its neighbors. Functionally, this minimizes VM depolarization attributable to elevated levels of local extracellular K+ and thereby maintains a sustained driving force for highly efficient K+ uptake. Thus, gap junction coupling functions to achieve isopotentiality in astrocytic networks, whereby a constant extracellular environment can be powerfully maintained for crucial functions of neural circuits.

Neuron-glia cross talk revealed in reverberating networks by simultaneous extracellular recording of spikes and astrocytes' glutamate transporter and K+ currents

“…Between 2 and 10 DIV, the frequency of positive sP events decreased, whereas the amplitude of negative sPs dramatically increased, along with SR and burst frequency (see also Sun et al 2010). The presence of sP waveforms of opposite polarity matching the local presence or absence of spikes is consistent with the assumptions of the spatial K + buffering model, which is based on the electrical syncytial properties of the glial network (Kofuji and Newman 2004; Ma et al 2016). Moreover, the observation that fast negative and late positive sPs were detected with spatiotemporal precision of 200 μm/0.7 s (Fig.…”

“…These mechanisms are often assumed to be operant in other CNS regions but are still not demonstrated (Ransom 1996). Nonetheless, recent work in hippocampal astrocytes has demonstrated syncytial isopotentiality ensuing from strong electrical coupling between astrocytes (Ma et al 2016). To capture the different electrophysiological aspects of this mechanism in neocortical tissue, we extended the MEA method to study the spatiotemporal properties of the neuron-glia cross talk in large networks (∼30,000 cells for ∼10 mm 2 ) and sample for weeks the cellular responses at timescales ranging from submilliseconds to minutes.…”

Syncytial isopotentiality: A system‐wide electrical feature of astrocytic networks in the brain

“…Although astrocytes have long been thought of as integral units of neural circuits, how astrocytes act as a system in brain function emerges as a current focus of research (Nimmerjahn & Bergles, ). One mechanism revealed in our recent study shows that a strong electrical coupling enables hippocampal astrocytes to constantly equalize their membrane potentials so that a syncytial isopotentiality can be achieved (Ma et al, ).…”

“…In mouse hippocampus, a strong interastrocytic electrical coupling and a minimum of 7–9 directly coupled nearest neighbors are two critical factors underpinning syncytial isopotentiality (Ma et al, ). However, it is yet unknown whether a combination of these structural and functional features would serve as a generic pattern of “astrocyte connectome” to underpin syncytial isopotentiality across the brain.…”

“…In doing so, CUBIC tissue clearing method was used to examine the morphology of different subtypes of astrocytes and their spatial organizations in Aldh1l1‐eGFP mice with high resolution (Susaki et al, , ). The existence of syncytial isopotentiality was examined by our newly developed methodology, which involves the use of K + ‐free/Na + ‐containing recording pipette solution (Ma et al, ).…”