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Astrocytes are the most abundant cell type in the mammalian brain. Interest in astrocyte function has increased dramatically in recent years because of their newly discovered roles in synapse formation, maturation, efficacy, and plasticity. However, our understanding of astrocyte development has lagged behind that of other brain cell types. We do not know the molecular mechanism by which astrocytes are specified, how they grow to assume their complex morphologies, and how they interact with and sculpt developing neuronal circuits. Recent work has provided a basic understanding of how intrinsic and extrinsic mechanisms govern the production of astrocytes from precursor cells and the generation of astrocyte diversity. Moreover, new studies of astrocyte morphology have revealed that mature astrocytes are extraordinarily complex, interact with many thousands of synapses, and tile with other astrocytes to occupy unique spatial domains in the brain. A major challenge for the field is to understand how astrocytes talk to each other, and to neurons, during development to establish appropriate astrocytic and neuronal network architectures.

Calcium signalling in astrocytes, driven through the octopamine/tyramine receptor and the TRP channel Water witch, is essential for neuromodulation and sensory responses in Drosophila larvae. Behaviour linked to astrocyte calcium signalling Calcium signalling in glial cells has been proposed to participate in neuronal function but evidence has remained indirect and scattered. Now Marc Freeman and colleagues report that the octopamine/tyramine receptor (Oct-Tyr-R) and the transient receptor potential (TRP) channel Water witch (Wtrw) in Drosophila astrocytes are essential to neuromodulation between two classes of neurons, and to sensory-driven larval behaviour. This is the first in vivo demonstration of astrocyte calcium signalling as an obligatory intermediate in neuronal circuitry and animal behaviour. Astrocytes associate with synapses throughout the brain and express receptors for neurotransmitters that can increase intracellular calcium (Ca 2+ ) 1 , 2 , 3 . Astrocytic Ca 2+ signalling has been proposed to modulate neural circuit activity 4 , but the pathways that regulate these events are poorly defined and in vivo evidence linking changes in astrocyte Ca 2+ levels to alterations in neurotransmission or behaviour is limited. Here we show that Drosophila astrocytes exhibit activity-regulated Ca 2+ signalling in vivo . Tyramine and octopamine released from neurons expressing tyrosine decarboxylase 2 (Tdc2) signal directly to astrocytes to stimulate Ca 2+ increases through the octopamine/tyramine receptor (Oct-TyrR) and the transient receptor potential (TRP) channel Water witch (Wtrw), and astrocytes in turn modulate downstream dopaminergic neurons. Application of tyramine or octopamine to live preparations silenced dopaminergic neurons and this inhibition required astrocytic Oct-TyrR and Wtrw. Increasing astrocyte Ca 2+ signalling was sufficient to silence dopaminergic neuron activity, which was mediated by astrocyte endocytic function and adenosine receptors. Selective disruption of Oct-TyrR or Wtrw expression in astrocytes blocked astrocytic Ca 2+ signalling and profoundly altered olfactory-driven chemotaxis and touch-induced startle responses. Our work identifies Oct-TyrR and Wtrw as key components of the astrocytic Ca 2+ signalling machinery, provides direct evidence that octopamine- and tyramine-based neuromodulation can be mediated by astrocytes, and demonstrates that astrocytes are essential for multiple sensory-driven behaviours in Drosophila .

How astrocytes grow and integrate into neural circuits remains poorly defined. Zebrafish are well suited for such investigations, but bona fide astrocytes have not been described in this system. Here we characterize a zebrafish cell type that is remarkably similar to mammalian astrocytes that derive from radial glial cells and elaborate processes to establish their territories at early larval stages. Zebrafish astrocytes associate closely with synapses, tile with one another and express markers, including Glast and glutamine synthetase. Once integrated into circuits, they exhibit whole-cell and microdomain Ca2+ transients, which are sensitive to norepinephrine. Finally, using a cell-specific CRISPR–Cas9 approach, we demonstrate that fgfr3 and fgfr4 are required for vertebrate astrocyte morphogenesis. This work provides the first visualization of astrocyte morphogenesis from stem cell to post-mitotic astrocyte in vivo, identifies a role for Fgf receptors in vertebrate astrocytes and establishes zebrafish as a valuable new model system to study astrocyte biology in vivo.Chen et al. define previously unreported zebrafish astrocytes, provide new insights into vertebrate astrocyte development and lay the foundation for studying astrocyte function in the entire nervous system of an intact and behaving animal.

Physiological performance declines precipitously at high body temperature (Tb), but little attention has been paid to adaptive variation in upper Tb limits among endotherms. We hypothesized that avian maximum tolerable Tb (Tbmax) has evolved in response to climate, with higher Tbmax in species exposed to high environmental heat loads or humidity-related constraints on evaporative heat dissipation. To test this hypothesis, we compared Tbmax and related variables among 53 bird species at multiple sites in South Africa with differing maximum air temperature (Tair) and humidity using a phylogenetically informed comparative framework. Birds in humid, lowland habitats had comparatively high Tbmax (mean ± SD = 45.60 ± 0.58 °C) and low normothermic Tb (Tbnorm), with a significantly greater capacity for hyperthermia (Tbmax 2 Tbnorm gradient = 5.84 ± 0.77 °C) compared with birds occupying cool montane (4.97 ± 0.99 °C) or hot arid (4.11 ± 0.84 °C) climates. Unexpectedly, Tbmax was significantly lower among desert birds (44.65 ± 0.60 °C), a surprising result in light of the functional importance of hyperthermia for water conservation. Our data reveal a macrophysiological pattern and support recent arguments that endotherms have evolved thermal generalization versus specialization analogous to the continuum among ectothermic animals. Specifically, a combination of modest hyperthermia tolerance and efficient evaporative cooling in desert birds is indicative of thermal specialization, whereas greater hyperthermia tolerance and less efficient evaporative cooling among species in humid lowland habitats suggest thermal generalization.

Critical periods—brief intervals during which neural circuits can be modified by activity—are necessary for proper neural circuit assembly. Extended critical periods are associated with neurodevelopmental disorders; however, the mechanisms that ensure timely critical period closure remain poorly understood 1 , 2 . Here we define a critical period in a developing Drosophila motor circuit and identify astrocytes as essential for proper critical period termination. During the critical period, changes in activity regulate dendrite length, complexity and connectivity of motor neurons. Astrocytes invaded the neuropil just before critical period closure 3 , and astrocyte ablation prolonged the critical period. Finally, we used a genetic screen to identify astrocyte–motor neuron signalling pathways that close the critical period, including Neuroligin–Neurexin signalling. Reduced signalling destabilized dendritic microtubules, increased dendrite dynamicity and impaired locomotor behaviour, underscoring the importance of critical period closure. Previous work defined astroglia as regulators of plasticity at individual synapses 4 ; we show here that astrocytes also regulate motor circuit critical period closure to ensure proper locomotor behaviour. The duration of a critical period of plasticity in the developing Drosophila motor circuit, during which motor neurons display activity-dependent refinement of neurite structure and connectivity, is dependent on astrocyte to motor neuron Neuroligin–Neurexin signalling.

Astrocytes exhibit spatially-restricted near-membrane microdomain Ca 2+ transients in their fine processes. How these transients are generated and regulate brain function in vivo remains unclear. Here we show that Drosophila astrocytes exhibit spontaneous, activity-independent microdomain Ca 2+ transients in their fine processes. Astrocyte microdomain Ca 2+ transients are mediated by the TRP channel TrpML, stimulated by reactive oxygen species (ROS), and can be enhanced in frequency by the neurotransmitter tyramine via the TyrRII receptor. Interestingly, many astrocyte microdomain Ca 2+ transients are closely associated with tracheal elements, which dynamically extend filopodia throughout the central nervous system (CNS) to deliver O 2 and regulate gas exchange. Many astrocyte microdomain Ca 2+ transients are spatio-temporally correlated with the initiation of tracheal filopodial retraction. Loss of TrpML leads to increased tracheal filopodial numbers, growth, and increased CNS ROS. We propose that local ROS production can activate astrocyte microdomain Ca 2+ transients through TrpML, and that a subset of these microdomain transients promotes tracheal filopodial retraction and in turn modulate CNS gas exchange.

Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Here, we show that loss of the Drosophila Toll receptor adaptor dSarm (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway.

Actin, spectrin, and associated molecules form a periodic, submembrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal- and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: Spectrin shows a long-range, periodic distribution throughout all axons but appears periodic only in a small fraction of dendrites, typically in the form of isolated patches in subregions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is disrupted in most presynaptic boutons but is present in an appreciable fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus, and Homo sapiens.

Uptake of the neurotransmitter GABA by transporters called GATs is known to influence neuronal GABAergic tone. Here Muthukumar et al . show that the wave of synaptogenesis in Drosophila brains occurs during the second half of pupal development in an astrocyte-dependent manner. The study also shows that the upregulation of GAT during this process requires astrocytic metabotropic GABA receptors, and this pathway mediates mechanosensory-induced seizure activity in GABAergic mutants with hyperexcitable neurons. Astrocytic uptake of GABA through GABA transporters (GATs) is an important mechanism regulating excitatory/inhibitory balance in the nervous system; however, mechanisms by which astrocytes regulate GAT levels are undefined. We found that at mid-pupal stages the Drosophila melanogaster CNS neuropil was devoid of astrocyte membranes and synapses. Astrocyte membranes subsequently infiltrated the neuropil coordinately with synaptogenesis, and astrocyte ablation reduced synapse numbers by half, indicating that Drosophila astrocytes are pro-synaptogenic. Shortly after synapses formed in earnest, GAT was upregulated in astrocytes. Ablation or silencing of GABAergic neurons or disruption of metabotropic GABA receptor 1 and 2 (GABA B R1/2) signaling in astrocytes led to a decrease in astrocytic GAT. Notably, developmental depletion of astrocytic GABA B R1/2 signaling suppressed mechanosensory-induced seizure activity in mutants with hyperexcitable neurons. These data reveal that astrocytes actively modulate GAT expression via metabotropic GABA receptor signaling and highlight the importance of precise regulation of astrocytic GAT in modulation of seizure activity.

Astrocytes are important regulators of neural circuit function and behavior in the healthy and diseased nervous system. We screened for molecules in Drosophila astrocytes that modulate neuronal hyperexcitability and identified multiple components of focal adhesion complexes (FAs). Depletion of astrocytic Tensin, β-integrin, Talin, focal adhesion kinase (FAK), or matrix metalloproteinase 1 (Mmp1), resulted in enhanced behavioral recovery from genetic or pharmacologically induced seizure. Overexpression of Mmp1, predicted to activate FA signaling, led to a reciprocal enhancement of seizure severity. Blockade of FA-signaling molecules in astrocytes at basal levels of CNS excitability resulted in reduced astrocytic coverage of the synaptic neuropil and expression of the excitatory amino acid transporter EAAT1. However, induction of hyperexcitability after depletion of FA-signaling components resulted in enhanced astrocyte coverage and an approximately twofold increase in EAAT1 levels. Our work identifies FA-signaling molecules as important regulators of astrocyte outgrowth and EAAT1 expression under normal physiological conditions. Paradoxically, in the context of hyperexcitability, this pathway negatively regulates astrocytic process outgrowth and EAAT1 expression, and their blockade leading to enhanced recovery from seizure.