Exciting roles of non‐excitable cells in the brain and heart

The brain and heart are organs whose main function depends on electrical excitation, made possible by populations of excitable cells. In both, however, there are also large populations of non-excitable cells that are integral to the organ's normal electrical activity and can be drivers or mitigators of detrimental changes that occur with disease. For instance, in the brain, glial and endothelial cells are engaged in neurotransmission (Allen & Lyons, 2018), formation and maintenance of the blood–brain barrier (Alvarez et al., 2013), and responses to nerve damage or infection (Greenhalgh et al., 2020), while in the heart, fibroblasts (Quinn et al., 2016) and immune cells (Hulsmans et al., 2017) may electrically couple to cardiomyocytes and directly influence their electrical activity in both physiological and pathophysiological conditions (Simon-Chica et al., 2023). The growing recognition of the fundamental importance of non-excitable cells in supporting excitable organ function is further evidenced by the substantial increase in related publications over the past few decades. For instance, research on glia (non-neuronal cells of the brain and nervous system, which were originally thought to solely provide structural support but are now known to be active participants in neuronal function) has increased approximately threefold between 1995 and 2025, encompassing more than 85,900 studies about their role in brain function, and even over 1150 studies examining their contribution in the heart (Fig. 1). Nevertheless, much remains to be understood about the biology of non-excitable cells and their interactions among diverse subtypes and with excitable cells in the brain and heart, as well as their potential as therapeutic targets in disease. This special issue of The Journal of Physiology illuminates the pivotal role of non-excitable cells for the electrical function of the brain and heart. Bringing together peer-reviewed Topical Reviews and Original Research Articles, it advances our understanding of how diverse cell types coordinate to sustain brain and heart physiology in the face of dynamic internal and external challenges. The collection features papers highlighting fundamental mechanisms underlying non-excitable cell function, complex dynamics of intercellular communication and their contribution to the integrative electrical activity of the brain and heart, and the involvement of non-excitable cells in the heart–brain axis, examined across multiple spatial and temporal scales in both health and disease. The collection opens with a systematic review by Chiappini et al. (2025), which presents an in-depth examination of the ultrastructure of astrocytes, the most abundant glia cells in the brain. With their intricate, bushy morphology and fine peri-synaptic processes, astrocytes play a central role in regulating synaptic function and information flow in the brain. Yet, visualising these fine structures remains technically challenging as traditional light microscopy lacks sufficient resolution, and widely used immunostaining with the astrocyte-specific glial fibrillary acidic protein (GFAP) labels only a fraction of astrocytes. The authors discuss how cutting-edge volume electron microscopy combined with advanced analytical approaches is enabling us to answer fundamental questions regarding astrocyte spatial distribution, synaptic coverage, and regional and interspecies heterogeneity that shape their functional diversity. Continuing with the theme of astrocyte heterogeneity, Dias et al. (2025) delve into the realm of astrocyte physiology, reviewing the dynamic role of astrocytic metabotropic glutamate receptor 5 (mGluR5) in neuron–glia communication. The authors argue that astrocytic mGluR5 serves as a dynamic modulator of neuronal circuits, whose dysregulation may both drive and attenuate neuropathological processes, highlighting the importance of studying its signalling mechanisms and therapeutic potential. Mastitskaya et al. (2025) then provide a comprehensive overview of glia cells in the heart, demonstrating their indispensable role in maintaining its electrical stability and modulating cardiac rhythm and contractility. The authors discuss in detail the fundamental roles of Schwann cells in heart repair, including their contribution to the development of arrhythmias after myocardial infarction; the importance of satellite glia cells for regulating neurotransmitter and ion homeostasis in the heart, through mechanisms involving ATP, glutamate and others; and the contribution of recently discovered cardiac nexus glia to maintaining the cardiac micro-environment, by regulating neurotransmitter levels and clearing tissue debris. The following articles in the special issue focus on dissecting intercellular interactions in the brain, including circuit-wide integration of astrocytes and neurons, the astrocyte–microglia and oligodendrocyte–microglia nexus in neurodegenerative disease, and glia-dependent mechanisms driving neuronal excitability in epilepsy. Hatashita and Inoue (2025) first discuss optical, genetic and viral approaches for interrogating circuit-specific astrocyte populations. In line with recent advances in understanding astrocyte heterogeneity, their paper presents novel strategies to map distinct astrocyte functions within defined neuronal circuits, offering innovative frameworks to integrate the anatomical organisation of astrocyte–neuron networks and the diversity of inter- and intra-regional circuitry. Mitchener et al. (2025) then present compelling evidence – driven by results from recent single cell transcriptomic studies – suggesting that both micro- and macroglia (astrocytes and oligodendrocytes) actively participate in immune signalling in neurodegenerative disease. Finally, Barath and Wu (2025) further discuss the role of microglia subtypes and their associated signalling pathways in epilepsy, followed by a study from Wu, Henning et al. (2025) expanding this line of research, which presents original findings demonstrating that astrocyte death in epilepsy is mediated by TNFR1 regulation through RIPK1, RIPK3, and MLKL. The next set of articles move to the heart, focusing on the importance of cardiac heterocellular interactions for electrical conduction, how they may be explored using computational modelling, their role in creating an arrhythmogenic substrate, and how they may be targeted for novel anti-arrhythmic therapies. In their review, Wu, Payne et al. (2025) challenge the long-held understanding that coupling of cardiomyocytes by gap junctions is the primary means of electrical propagation in the heart by presenting available evidence demonstrating the importance of heterocellular gap junctional coupling, as well as ephaptic coupling, for cardiac conduction and electrical dysfunction in disease. This is followed by a review from Simon-Chica et al. (2025), discussing the utility of computational models for studying these heterocellular electrical interactions, including electrotonic influences of fibroblasts and macrophages on cardiac electrophysiology across multiple spatial scales. These two studies – and how they present a challenge to our current understanding of cardiac electrical propagation – are then highlighted in an accompanying perspective by Grune et al. (2025), which further discusses the complex heterocellular nature of cardiac electrophysiology and how emerging insights are being driven by novel technologies. Next is a review by Dong et al. (2025), focused specifically on the role of cellular and molecular cross-talk in creating an arrhythmogenic substrate for atrial fibrillation initiation and perpetuation, specifically the interplay between fibroblasts, adipocytes, inflammatory cells and the coagulation system, and their impact on cardiomyocyte electrical function. Finally, Mohr et al. (2025) present an original study testing the utility of magnetically steering moloney murine leukaemia virus complexed with magnetic nanoparticles for the targeted genetic transduction of resident cardiac (myo)fibroblasts after myocardial infarction in vivo. They show that the overexpression of gap junction protein connexin 43 in fibroblasts by this method increases the formation of functional gap junctions and lowers post-injury ventricular tachycardia incidence. The final two articles of the special issue highlight the importance of non-excitable cells for cardiovascular–brain interactions. First, Parker et al. (2025) present evidence on how cerebral amyloid-beta and tau deposition, which impair cognition in Alzheimer's disease, may not only be a consequence of cardiovascular dysfunction but also may contribute to cardiovascular complications – including cardiac arrhythmias – by affecting cardiac fibrosis, electrophysiology, contractility, autonomic regulation, and vasomotor tone. Then Christie (2025) discusses astrocyte contributions to the regulation of brain gas exchange, through intricate mechanisms of blood oxygen and brain proton sensing and subsequent alterations of blood vessel diameter via release of vasoactive agents. The author also discusses the role of astrocytes in regulating cerebral perfusion, particularly reductions associated with ageing and neurological conditions, and how these changes correlate with cognitive function. Overall, this collection highlights the current state of research related to the electrophysiological roles of non-excitable cells in the brain and heart, ultimately offering valuable perspectives for future discoveries in the field. While historically, investigations into brain and heart electrical function have predominantly focused on their excitable cells, recent studies reveal that their electrophysiology can be strongly affected by non-excitable cell populations, bringing glial and other supporting cells to the forefront of physiological research. We would like to thank all the contributing authors for their thorough and timely work and hope this issue will inspire and guide further innovation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare they have no competing interests. V.M. and T.A.Q. wrote the paper and agree to be accountable for all aspects of the work in ensuring that questions related to any part of its accuracy or integrity are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. The authors’ work is funded by: an Academy of Medical Sciences Springboard Award (SBF005∖1102 to V.M.); a Medical Research Council Career Development Award (MR/T031115/1 to V.M.); the Canadian Institutes of Health Research (PJT-190 009 to T.A.Q.); the Natural Sciences and Engineering Research Council of Canada (RGPIN-2022-0 3150 to T.A.Q.); and the Heart and Stroke Foundation of Canada (G-22-00 32127 to T.A.Q.).