Special issue editorial: Glial plasticity in health and disease

Abstract

Recent decades bear witness to the Renaissance in glial research. The concept of neuroglia introduced by Rudolf Virchow in 1850s (Virchow, 1856) has been in the sights of every major neuroanatomist of 19th and early 20th century (Chvatal & Verkhratsky, 2018; Lenhossek, 1895; Lugaro, 1907; Ramon y Cajal, 1913; Sierra et al., 2016), whereas neuropathologists highlighted the leading role of neuroglia in neurological diseases (Alzheimer, 1910; del Río-Hortega & Penfield, 1927). The accelerated pace of glial research within modern neuroscience has highlighted diverse functions of astrocytes, oligodendrocytes, and microglia: these cells have dazzled with the amazing array of their roles in shaping the brain in development, ensuring its proper function during the lifespan, and contributing, both positively and negatively, to disease and injury processes. Most recently, it has become clear that immense heterogeneity exists within each glial population, which reflects the many diverse functions these cells perform (Foerster et al., 2019; Khakh & Deneen, 2019; Mendes & Majewska, 2021). Different glial phenotypes exist within different brain structures reflecting the different computations carried out throughout the brain. Morphological and genetic analyses have also made it evident that even within a single brain area glia are diverse, possibly reflecting differences in local environmental cues, or developmental trajectories of neighboring glial cells. Such differences may also be indicative of the different functions glial cells execute locally in the physiological and pathological brain. Astrocytes are the primary homeostatic cells of the central nervous system (CNS). Astroglial homeostatic support occurs at all levels of organization of the nervous system. At the molecular level, astrocytes are involved in the homoeostasis of ions, neurotransmitters, protons, reactive oxygen species, and metabolites. At the cellular level, astrocytes are the stem cells of the adult CNS. At the network level, astrocytes regulate synaptogenesis, synaptic maturation and extinction, supply neurons with neurotransmitter precursors, and metabolites. At the organ level, astrocytes control the blood–brain barrier, glymphatic flow, and regulate functional hyperemia. Finally, at the systemic level, astrocytes act as central chemoceptors and contribute to systemic control over ventilation, ion homeostasis, and energy metabolism (Verkhratsky & Nedergaard, 2018). Oligodendrocytes are the myelinating cells in the central nervous system (with Schwann cells serving this function peripherally), allowing miniaturization of white matter and ensuring fast signal propagation between distant parts of the neuronal network. While the activity of oligodendrocytes and their precursor cells in the setting of development and demyelinating injury has long been described, recent work has shown that myelination is remarkably plastic and can critically contribute to neuronal function throughout the lifespan (Kuhn et al., 2019). Unlike astrocytes and oligodendrocytes, microglia are born outside of the nervous system and migrate to the brain to adopt immune roles in this relatively immune privileged site. In the brain, microglia undergo a remarkable metamorphosis acquiring a highly ramified morphology and expressing receptors and transporters for neurotransmitters (Sierra et al., 2019). For a long time, microglia were studied mainly in the context of their reactive response in injury and disease. Recent studies, however, demonstrated that microglia critically contribute to many physiological brain functions throughout the lifespan (Mendes & Majewska, 2021). The studies that jump started the research into microglial roles in physiological settings showed that, in the absence of an immunological challenge, microglia are highly dynamic, surveilling the parenchyma, and extending their ramified process network at a remarkable rate of tens of microns an hour (Davalos et al., 2005; Nimmerjahn et al., 2005). Structural dynamics may be a common feature of glia, as dynamic changes in the morphology of astrocytes and oligodendrocyte precursor cell processes have been described in the physiological and pathological brain (Haber et al., 2006; Hughes et al., 2013). This ability to navigate the brain and interact with their environment (including their more stationary neuronal partners) may be critical to the diverse functions that these different glial cells play in the brain. With our evolving understanding of glial roles in the brain, it appears that glial cells contribute to almost every aspect of brain function, often exhibiting overlapping roles and complementary behaviors in response to Received: 25 July 2021 Revised: 29 July 2021 Accepted: 2 August 2021