Astrocytes regulate the formation and function of neuronal synapses via multiple signals; however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development is also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single-nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, highlighting astrocytes as a target to manipulate in neurodevelopmental disorders.

The brain is a highly adaptable organ that is molded by experience throughout life. Although the field of neuroscience has historically focused on intrinsic neuronal mechanisms of plasticity, there is growing evidence that multiple glial populations regulate the timing and extent of neuronal plasticity, particularly over the course of development. This review highlights recent discoveries on the role of glial cells in the establishment of cortical circuits and the regulation of experience-dependent neuronal plasticity during critical periods of neurodevelopment. These studies provide strong evidence that neuronal circuit maturation and plasticity are non-cell autonomous processes that require both glial–neuronal and glial–glial cross talk to proceed. We conclude by discussing open questions that will continue to guide research in this nascent field.

Behavior arises from coordinated brain-wide neural and glial networks, enabling organisms to perceive, interpret, and respond to stimuli. Astrocytes play an important role in shaping behavioral output, yet the underlying molecular mechanisms are not fully understood. Astrocytes respond to intrinsic and extrinsic cues with calcium (Ca²⁺) fluctuations, which are highly heterogeneous across spatio-temporal scales, contexts, and brain regions. This heterogeneity allows astrocytes to exert dynamic regulatory effects on neuronal function but has made it challenging to understand the precise mechanisms and pathways linking astrocytic Ca²⁺ to specific behavioral outcomes, and the functional relevance of these signals remains unclear. Here, we review recent literature uncovering roles for astrocytic Ca²⁺ signaling in a wide array of behaviors, including cognitive, homeostatic, and affective focusing on its physiological roles, and potential pathological implications. We specifically highlight how different types of astrocytic Ca²⁺ signals are linked to distinct behavioral outcomes and discuss limitations and unanswered questions that remain to be addressed.

Summary: Astrocytes regulate the formation and function of neuronal synapses via multiple signals, however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually-evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development are also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, identifying astrocytes as a target to manipulate in neurodevelopmental disorders.

Neuronal injury due to trauma or neurodegeneration is a common feature of aging. The clearance of damaged neurons by glia is thought to be critical for maintenance of proper brain function. Sleep loss has been shown to inhibit the motility and function of glia that clear damaged axons while enhancement of sleep promotes clearance of damaged axons. Despite the potential role of glia in maintenance of brain function and protection against neurodegenerative disease, surprisingly little is known about how sleep loss impacts glial function in aged animals. Axotomy of the Drosophila antennae triggers Wallerian degeneration, where specialized olfactory ensheathing glia engulf damaged neurites. This glial response provides a robust model system to investigate the molecular basis for glial engulfment and neuron-glia communication. Glial engulfment is impaired in aged and sleep-deprived animals, raising the possibility that age-related sleep loss underlies deficits in glial function. To define the relationship between sleep- and age-dependent reductions in glial function, we used two complementary approaches to enhance sleep in aged animals and examined the effects on glial clearance of damaged axons. Both pharmacological and genetic induction of sleep restores clearance of damaged neurons in aged flies. Further analysis revealed that sleep restored post-injury induction of the phagocytic protein Draper to aged flies, fortifying the notion that loss of sleep contributes to reduced glial-mediated debris clearance in aged animals. To identify age-related changes in the transcriptional response to neuronal injury, we used single-nucleus RNA-seq (snRNA-seq) of the central brains from axotomized young and old flies. We identified broad transcriptional changes within the ensheathing glia of young flies, and the loss of transcriptional induction of autophagy-associated genes. We also identify age-dependent loss of transcriptional induction of 18 transcripts encoding for small and large ribosomal protein subunits following injury in old flies, suggesting dysregulation of ribosomal biogenesis contributes to loss of glial function. Together, these findings provide further support for a functional link between sleep loss, aging and Wallerian degeneration.