Astrocytes, ATP, Brainstem, and Breathing: Astrocytes (or glial cells), previously assumed to be passive players in brain physiology, may play a functional role in a number of complex behaviors. The central chemosensory control of breathing involves highly specialized neuronal populations in the brainstem, but what about astrocytes? Gourine et al. (p. 571 , published online 15 July) now present evidence that glial cells may help to control breathing. A number of techniques were used to reveal glial calcium rises in vitro that elicit a depolarization of neurons in the primary locus for central respiratory chemosensitivity. The depolarization in these neurons is evoked by vesicular release of ATP in neighboring astrocytes in response to the fall in extracellular pH. Thus, brainstem astrocytes have the ability to sense changes in blood and brain CO ₂ , and pH directly, and may control the activity of the respiratory neuronal networks to regulate breathing.

Astrocytes produce and releaseL-lactate as a potential source of energy for neurons. Here we present evidence thatL-lactate, independently of its caloric value, serves as an astrocytic signalling molecule in the locus coeruleus (LC). The LC is the principal source of norepinephrine to the frontal brain and thus one of the most influential modulatory centers of the brain. Optogenetically activated astrocytes releaseL-lactate, which excites LC neurons and triggers release of norepinephrine. ExogenousL-lactate within the physiologically relevant concentration range mimics these effects.L-lactate effects are concentration-dependent, stereo-selective, independent ofL-lactate uptake into neurons and involve a cAMP-mediated step.In vivoinjections ofL-lactate in the LC evokes arousal similar to the excitatory transmitter,L-glutamate. Our results imply the existence of an unknown receptor for this ‘glio-transmitter’.

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply^1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism^3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood^5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3′,5′-monophosphate–protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.

In the brain, L-lactate is produced by both neurons and astrocytes. There is no doubt that neurons use L-lactate as a supplementary fuel although the importance of this energy source is disputed. Irrespective of its caloric value, L-lactate might also have a signaling role in the brain. Here, we review several current hypotheses of L-lactate mediated signaling. Some proposed mechanisms require L-lactate entry into the neurons leading to a shift in ATP/ADP ratio or redox state. Others postulate interaction with either known receptor HCA1 (GPR81) or a novel, yet unidentified receptor. We argue that the sensitivity of any such mechanism has to match the concentration range of extracellular L-lactate, which is less than ~ 1.5 mmol/L under physiologic conditions. From that point of view, some of the proposed mechanisms require supraphysiologic levels of L-lactate and could be engaged during ischemia or seizures when L-lactate concentration rises dramatically. Currently, we do not know whether L-lactate production in the brain occurs in microdomains, which might create higher than average local concentrations. Nevertheless, it is clear that in the brain, as in the peripheral tissues, L-lactate is not only used as a source of energy but also acts as a signaling molecule.

Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

Genetically encoded sensors developed on the basis of green fluorescent protein (GFP)-like proteins are becoming more and more popular instruments for monitoring cellular analytes and enzyme activities in living cells and transgenic organisms. In particular, a number of Ca2+ sensors have been developed, either based on FRET (Fluorescence Resonance Energy Transfer) changes between two GFP-mutants or on the change in fluorescence intensity of a single circularly permuted fluorescent protein (cpFP).