Trends in Neurosciences
ReviewAstrocyte–neuron metabolic relationships: for better and for worse
Introduction
Astrocytes have unique cytoarchitectural and phenotypic features that ideally position them to sense their surroundings and dynamically respond to changes in their microenvironment (Figure 1). They extend numerous processes (Figure 1a,b), forming highly organized anatomical domains with little overlap between adjacent cells (referred to as ‘astrocytic domains’; Figure 1e) and are interconnected into functional networks via gap junctions (Figure 1f). Some astrocyte processes (which express a wide range of receptors and ion channels) closely ensheath synapses (Figure 1c), whereas others are in close contact with intraparenchymal blood vessels via specialized processes called endfeet (Figure 1d). In line with this, astrocytes have been shown to play an important role in neurovascular and neurometabolic coupling. Indeed, neuronal activity triggers the release of vasoactive substances by astrocytes, such as prostanoids, enabling the dynamic coupling of cerebral blood flow with the local energy demand 1, 2. At the metabolic level, as formulated by the astrocyte–neuron lactate shuttle model (ANLS), astrocytes respond to glutamatergic activation by increasing their rate of glucose utilization and the release of lactate in the extracellular space, which might, in turn, be used by neurons to sustain their energy demands 3, 4 (Box 1; Figure 2, green pathway).
Several other homeostatic functions of astrocytes have been demonstrated, including glutamate, ion and water homeostasis, defense against oxidative stress, energy storage in the form of glycogen, scar formation and tissue repair, modulation of synaptic activity via the release of gliotransmitters, and synapse formation and remodeling (reviewed in 5, 6, 7, 8). Interestingly, recent evidence has shed light on previously unsuspected roles of astrocytes in higher brain functions, such as sleep homeostasis [9], memory consolidation [10] and in the regulation of breathing [11]. Some of the key homeostatic functions of astrocytes representative of their strong metabolic relationship with neurons are illustrated in Figure 2. In addition to these metabolic functions, astrocytes release several factors that sustain neuronal function and viability (Box 1). Interestingly, astrocytes are known to be a heterogenous cell population based on their morphology and the expression of different sets of receptors, transporters, ions channels and other proteins [12]. This raises the intriguing possibility that different subtypes of astrocyte are implicated in distinct metabolic/homeostatic functions.
Considering the pivotal role of astrocytes in brain homeostasis and the strong metabolic cooperation that exists between neurons and astrocytes, one would predict that astrocytic dysfunction might cause and/or contribute to neurodegenerative processes. In line with this, a growing body of evidence points to an important role of astrocytes in several pathologies, either through loss of normal function, or gain of defective functions. This review focuses on recent evidence highlighting the importance of astrocytes in selected pathologies and discusses how re-establishing or enhancing normal astrocytic functions might be a valuable strategy to promote neuroprotection in various central nervous system (CNS) disorders.
Section snippets
Primary astroglial diseases
Direct evidence for pivotal roles of astrocytes in maintaining normal brain function is provided by neurological disorders that are primarily caused by a dysfunction of these cells. Not surprisingly, these pathologies generally affect a wide range of cerebral processes owing to secondary malfunction of other cell types, including neurons, microglia and oligodendrocytes.
A striking example is Alexander disease (AXD), the first identified human neurological disorder unequivocally caused by a
Other pathologies involving astrocytes
In addition to the abovementioned primary astroglial disorders, disturbances of astrocytic functions have been shown to contribute, along with other neural cell types, to the development and progression of several other neuropathologies for which the primary cause might not have yet been identified (Table 1). Recent evidence highlighting the active role of astrocytes in neuroinflammation, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are discussed below.
Perspectives
As described above, considering the numerous cellular interactions between astrocytes and neurons (Figure 2, Box 1), it is evident that defects of astrocytic functions and/or alterations of astrocyte–neuron cooperativity might lead to neuronal damage. Consistent with this, it has become obvious that enhancing or re-establishing astrocytic functions could represent a valuable strategy for neuroprotection. In vitro evidence of such neuroprotective actions has been obtained by enhancing the
Concluding remarks
As discussed in this review, the study of the role of astrocytes in physiological and pathophysiological processes is a rapidly expanding field of research. Such studies largely rely on the development of new technologies that enable the contribution of specific cell types to various brain functions to be dissected. Although compelling evidence points to a role of astrocytes in various pathologies, it must be emphasized that, in many cases, the primary cause of the disease has not been clearly
Acknowledgments
The authors would like to thank Thierry Laroche (BioImaging and Optics Core Facility, EPFL) for his contribution. This work was supported by a grant from the Swiss National Science Foundation (FNRS) to P.J.M. (no. 3100AO-108336/1). M.B. was supported by a fellowship from the Fonds de la Recherche en Santé du Québec (FRSQ). P.J.M. is the recipient of the Asterion Foundation Chair.
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Contributed equally to this work.