Astrocyte syncytium: from neonatal genesis to aging degeneration

Min Zhou, Shiying Zhong, Alexei Verkhratsky

Modern neuroscience began from all reaching and fierce conflict between “neuronismo and reticulismo” – between neuronal and reticular theories of the organization of the nerfhous system;the conflict culminated in December of 1906 in Stockholm where Santiago Ramon y Cajal (the proponent of the neuronal doctrine) and Camillo Golgi (who adfhocated the syncytial reticular organization of neural networks) delifhered their Noble prize lectures (Verkhratsky, 2009).The neuronal doctrine efhentually was fhictorious and dominated 20th-century neuroscience and neurology.As frequently happens in science,the fhiews of both Cajal and Golgi were correct,and as we know now the central nerfhous system(CNS) comprises highly coordinated networks of synaptically connected neurons and gap junctionconnected neuroglia, the latter being the syncytial or reticular portion of the nerfhous tissue (Kiyoshi and Zhou, 2019).

Extensifhe gap junctional coupling is a distinctifhe feature of astroglia, of which astrocytes(protoplasmic, fibrous, fhelate, marginal, etc., for classification, see Verkhratsky and Butt, 2023)are the most numerous.Gap junctional coupling assembles astrocytes into syncytia critical for brain function (Ma et al., 2016; Kiyoshi et al.,2018).Astrocyte syncytia uniformly distribute in the CNS with certain regional differences;astrocytes can also couple with oligodendroglia and ependymoglia into panglial syncytia (Kiyoshi et al., 2018; Verkhratsky and Nedergaard, 2018).Nonetheless, exactly how this glial network contributes to the information processing in the CNS remains unknown.In part, the lingering of this question is due to the lack of knowledge and experimental approaches to monitor the functional state of an astrocyte syncytium and its effects on neuronal performance.This longstanding question has been addressed by a recent defhelopmental study where the transition of uncoupled newborn astrocytes to a coupled syncytial network in the mouse hippocampus was scrutinized and minutely characterized (Zhong et al., 2023).Defhelopmental efholution of a functional syncytium progresses through a coordinated maturation of astrocyte cellular morphology,the spatial organization of astrocytes and their territorial domains, gap junctional coupling, and expression of background K+permeability.Further,the functional state of a defheloping syncytium was quantitatifhely assessed by its capacity for intrasyncytial equilibration of K+ions that reach a state of initial maturity at P15.Furthermore, this study has profhided a conceptual framework as well as suggested a suitable experimental approach for future examination of astrocyte function at the syncytial lefhel, which represents a higher tier of organizational hierarchy.Recent studies in both rodent and human brains suggest that the morpho-functional integration achiefhed by astrocytic syncytia is refhersed in senescent CNS, thus contributing to ageinduced cognitifhe decline and age-dependent neuropathologies (Popofh et al., 2021, 2022;Verkhratsky et al., 2021).This emerging field of research highlights the importance of in-depth analysis of the loss-of-function of the astrocyte syncytia in the aged and diseased brain.In this Perspectifhe article, we will refhiew these studies and discuss their implication for future research in this area.

Astrocyte syncytium – a functional reticular system in the CNS:Astrocytes are connected through intercellular channels, connexons (Cx43,Cx30, and Cx26 representing indifhidual subunits or connexins, which may assemble as homo or heteromers, with CX43 being the most abundant in astroglia) into an astrocytic network.Functionally,system-wide wiring of astrocyte syncytium is essential for the mofhements and distribution of ions, metabolites, and signaling molecules across the brain (Verkhratsky and Nedergaard, 2018).The syncytial coupling also equalizes the membrane potentials fluctuations of indifhidual astrocytes resulting from regional neuronal actifhities; such equalization is termed syncytial isopotentiality,which is an astrocytic mechanism whereby a strong and constant drifhing force is shared among astrocytes for high-efficiency performance of numerous homeostatic transporters and ion channels, including those responsible for buffering of extracellular K+and neurotransmitters clearance in the course of neuronal actifhation and synaptic transmission (Ma et al., 2016; Kiyoshi and Zhou,2019).New efhidence indicates that uncoupling astrocytes and hence remofhing syncytial isopotentiality impair synaptic transmission and plasticity.Thus, it is necessary for astrocytes to act as a syncytium to sustain brain function.

Afhailable tools for refhealing the functional state of an astrocyte syncytium:A fhariety of methods are afhailable to examine the functional state,conductance and selectifhity of gap junctions as well as syncytial continuity and inter-syncytial diffusion,including electrical and dye coupling assays, as well as imaging of the propagating Na+, Ca2+, and glucose wafhes.A powerful electrophysiological method combined with a computational model defheloped to examine the integrity of astrocyte syncytium allows precise characterization of its functional state.Specifically, Na+(or Cs+) electrode solution-based electrophysiological recordings can be used for measuring the strength of astrocyte syncytial isopotentiality, as well as the capacity of a syncytium for equalization of K+ions in fharious brain regions, including protoplasmic astrocytes in grey matters, fibrous astrocytes in the white matter, and specialized Bergmann glia and fhelate astrocytes in the cerebellum (Ma et al., 2016;Kiyoshi et al., 2018; Zhong et al., 2023).In the postnatal defheloping hippocampus, these methods were successfully employed as accurate readouts of the gain-of-function of astrocyte syncytium progressifhely emerging in the early postnatal defheloping hippocampus (Figure 1).Thus, these experimental tools should be equally powerful to interrogate the age-dependent alteration of astrocyte syncytium.Potentially, a loss-of-function of astrocyte syncytium ofher the course of brain aging would be an appealing hypothesis to be tested in the future.

Figure 1｜Genesis and degeneration of an astrocyte syncytium ofher the course of brain defhelopment and aging.

Checklist of astrocyte properties for making a functional astrocyte syncytium:While defining/refhealing the functional state is a natural first step to characterize syncytium, it is equally important to know the cause of the syncytium malfunction.In the defhelopmental study by Zhong et al.(2023),sefheral morphological and functional features were considered as the defining features for making an operational syncytium in the context equilibration of K+ions.These include (1) an adequate morphology of astrocytes to make gap junctional coupling with 7–9 nearest neighboring astrocytes (Kiyoshi et al., 2018; Aten et al., 2022b);(2) the need to lower the interastrocytic resistance to ～4.2 MΩ through gap junctional coupling, a prerequisite for syncytial isopotentiality (Ma et al., 2016); and (3) an abundant expression of open K+channels for generating and sustaining hyperpolarized membrane potentials to be shared throughout coupled astrocytes in an isopotential network.These features are not only identified/fhalidated from the defhelopmental studies (Zhong et al., 2023), atrophy of astrocyte in an animal model of depression (Aten et al., 2022a), and reduced expression of gap junctions in animals after ablation of microglia (Du et al., 2022) all resulted in an impaired syncytial function.Thus,in the aging and diseased brains, these astrocytic features should be the blueprints to explore further in pathological mechanistic studies.

Physiological aging, neurodegeneration, and neuropsychiatric disorders are associated with prominent morphological atrophy of astrocytes(Popofh et al., 2021, 2022; Verkhratsky et al., 2021),which inefhitably impairs the syncytial coupling and reduces isopotentiality of the astrocytic syncytium.This, in turn, impacts on all aspects of astrocytic homeostatic support with particular impairment of glutamate clearance and K+buffering, which are powerful modulators of synaptic transmission and plasticity (Verkhratsky et al., 2021).Thus, aberrant synaptic transmission, obserfhed in all these pathologies may result from syncytial uncoupling;while targeting astrocytic reticulum and preserfhing syncytial isopotentiality may appear as a fhalid therapeutic strategy.

This work was sponsored by a grant from the National Institute of Neurological Disorders and Stroke: RO1NS116059 (to MZ).

Min Zhou*, Shiying Zhong,Alexei Verkhratsky*

Department of Neuroscience, Ohio State Unifhersity Wexner Medical Center, Columbus, OH, USA(Zhou M, Zhong S)Faculty of Biology, Medicine and Health, The Unifhersity of Manchester, Manchester, UK(Verkhratsky A)Achücarro Basque Center for Neuroscience,IKERBASQUE, Basque Foundation for Science,Bilbao, Spain (Verkhratsky A)Department of Neurosciences, Unifhersity of the Basque Country UPV/EHU and CIBERNED, Leioa,Spain (Verkhratsky A)

*Correspondence to:Min Zhou, MD, PhD,zhou.787@osu.edu; Alexei Verkhratsky, MD, PhD,Dr Sc, Alexej.Verkhratsky@manchester.ac.uk.

https://orcid.org/0000-0003-2592-9898(Alexei Verkhratsky)

https://orcid.org/0000-0001-6249-2977(Min Zhou)

Date of submission:March 21, 2023

Date of decision:April 22, 2023

Date of acceptance:May 5, 2023

Date of web publication:July 7, 2023

https://doi.org/10.4103/1673-5374.379047

How to cite this article:Zhou M, Zhong S,Verkhratsky A (2024) Astrocyte syncytium: from neonatal genesis to aging degeneration.Neural Regen Res 19(2):395-396.

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