In the vertebrate nervous system, myelination of axons for rapid impulse propagation requires the synthesis of large amounts of lipids and proteins by oligodendrocytes and Schwann cells. Myelin membranes are thought to be cell-autonomously assembled by these axon-associated glial cells. Here, we report the surprising finding that in normal brain development, a substantial fraction of the lipids incorporated into central nervous system (CNS) myelin are contributed by astrocytes. The oligodendrocyte-specific inactivation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), an essential coactivator of the transcription factor SREBP and thus of lipid biosynthesis, resulted in significantly retarded CNS myelination; however, myelin appeared normal at 3 months of age. Importantly, embryonic deletion of the same gene in astrocytes, or in astrocytes and oligodendrocytes, caused a persistent hypomyelination, as did deletion from astrocytes during postnatal development. Moreover, when astroglial lipid synthesis was inhibited, oligodendrocytes began incorporating circulating lipids into myelin membranes. Indeed, a lipid-enriched diet was sufficient to rescue hypomyelination in these conditional mouse mutants. We conclude that lipid synthesis by oligodendrocytes is heavily supplemented by astrocytes in vivo and that horizontal lipid flux is a major feature of normal brain development and myelination. The myelin membrane is a highly specialized plasma membrane that enwraps axons, acts as an insulator, and is thus important for fast conduction of action potentials. It is thereby critical for proper functioning of the nervous system. Myelin in the central nervous system is synthesized by oligodendrocytes. Because myelin has a high lipid content, it is vulnerable to lipid metabolism disorders. It is unknown whether extracellular lipids also contribute to myelination by oligodendrocytes under healthy conditions, and if they do, what the origin of these lipids would be. Here, we show that formation of myelin membrane in mice does not only need lipid synthesis by oligodendrocytes, but also requires extracellular lipids provided by astrocytes. Indeed, when lipid synthesis was inactivated in either oligodendrocytes or astrocytes, myelin membrane synthesis was reduced. However, when lipid synthesis was inactivated in both cell types, myelin membrane synthesis was virtually absent. Furthermore, when lipid synthesis was inactivated in astrocytes, oligodendrocytes bypassed this deficiency by using dietary lipids for myelin membrane synthesis. Furthermore, a high-fat diet could promote myelin synthesis. We conclude that extracellular lipids, either provided by astrocytes or in the diet, contribute to myelination by oligodendrocytes during normal brain development.

Early‐life adversity (ELA) in the form of stress, inflammation, or malnutrition, can increase the risk of developing psychopathology or cognitive problems in adulthood. The neurobiological substrates underlying this process remain unclear. While neuronal dysfunction and microglial contribution have been studied in this context, only recently the role of astrocytes in early‐life programming of the brain has been appreciated. Astrocytes serve many basic roles for brain functioning (e.g., synaptogenesis, glutamate recycling), and are unique in their capacity of sensing and integrating environmental signals, as they are the first cells to encounter signals from the blood, including hormonal changes (e.g., glucocorticoids), immune signals, and nutritional information. Integration of these signals is especially important during early development, and therefore we propose that astrocytes contribute to ELA induced changes in the brain by sensing and integrating environmental signals and by modulating neuronal development and function. Studies in rodents have already shown that ELA can impact astrocytes on the short and long term, however, a critical review of these results is currently lacking. Here, we will discuss the developmental trajectory of astrocytes, their ability to integrate stress, immune, and nutritional signals from the early environment, and we will review how different types of early adversity impact astrocytes.

The mammalian CNS is considered to be autonomous in lipid metabolism. Glial cells, in particular astrocytes, have been shown to be highly active in lipid synthesis and secretion. To determine the importance of astrocytes as lipid providers in the brain, we generated mice in which the sterol regulatory element‐binding protein (SREBP) cleavage‐activating protein (SCAP) was deleted from astrocytes using cre/lox technology. SCAP mutant mice showed microcephaly, without effects on astrocyte survival. SCAP deletion in astrocytes led to a loss of cholesterol and fatty acid synthesis pathways. SCAP mutants showed progressive motor deficits, dyskinesia, and reduced anxiety. Interestingly, SCAP mutants showed changes in brain sterol and fatty acid profiles that were concordant with reduced lipid synthesis as well as with increased uptake of dietary lipids. Accordingly, a high‐fat diet rich in cholesterol and monounsaturated fatty acids, but not a fish oil diet rich in polyunsaturated fatty acids, improved motor deficits and survival of the mutant mice. These observations establish a critical role for astrocytes in brain lipid metabolism and demonstrate that dietary lipids can rescue astrocyte‐mediated lipid deficiency. The ability to correct these neurological deficits suggests that lipid supplementation may serve as a treatment for brain disorders associated with defective astrocyte lipid synthesis. —Camargo, N., Brouwers, J. F., Loos, M., Gutmann, D. H., Smit, A. B., Verheijen, M. H. G. High‐fat diet ameliorates neurological deficits caused by defective astrocyte lipid metabolism. FASEB J. 26, 4302–4315 (2012). www.fasebj.org

The formation and retrieval of fear memories depends on orchestrated synaptic activity of neuronal ensembles within the hippocampus, and it is becoming increasingly evident that astrocytes residing in the environment of these synapses play a central role in shaping cellular memory representations. Astrocyte distal processes, known as leaflets, fine-tune synaptic activity by clearing neurotransmitters and limiting glutamate diffusion. However, how astroglial synaptic coverage contributes to mnemonic processing of fearful experiences remains largely unknown. We used electron microscopy to observe changes in astroglial coverage of hippocampal synapses during consolidation of fear memory in mice. To manipulate astroglial synaptic coverage, we depleted ezrin, an integral leaflet-structural protein, from hippocampal astrocytes using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing. Next, a combination of Föster resonance energy transfer analysis, genetically encoded glutamate sensors, and whole-cell patch-clamp recordings was used to determine whether the proximity of astrocyte leaflets to the synapse is critical for synaptic integrity and function. We found that consolidation of a recent fear memory is accompanied by a transient retraction of astrocyte leaflets from hippocampal synapses and increased activation of NMDA receptors. Accordingly, astrocyte-specific depletion of ezrin resulted in shorter astrocyte leaflets and reduced astrocyte contact with the synaptic cleft, which consequently boosted extrasynaptic glutamate diffusion and NMDA receptor activation. Importantly, after fear conditioning, these cellular phenotypes translated to increased retrieval-evoked activation of CA1 pyramidal neurons and enhanced fear memory expression. Together, our data show that withdrawal of astrocyte leaflets from the synaptic cleft is an experience-induced, temporally regulated process that gates the strength of fear memories.

Over the last decade, the importance of astrocyte-neuron communication in neuronal development and synaptic plasticity has become increasingly clear. Since neuron-astrocyte interactions represent highly dynamic and reciprocal processes, we hypothesized that many astrocyte genes may be regulated as a consequence of their interactions with maturing neurons. In order to identify such neuron-responsive astrocyte genes in vitro, we sought to establish an expedite technique for separation of neurons from co-cultured astrocytes. Our newly established method makes use of cold jet, which exploits different adhesion characteristics of subpopulations of cells (Jirsova et al., 1997), and is rapid, performed under ice-cold conditions and avoids protease-mediated isolation of astrocytes or time-consuming centrifugation, yielding intact astrocyte mRNA with approximately 90% of neuronal RNA removed. Using this purification method, we executed genome-wide profiling in which RNA derived from astrocyte-only cultures was compared with astrocyte RNA derived from differentiating neuron-astrocyte co-cultures. Data analysis determined that many astrocytic mRNAs and biological processes are regulated by neuronal interaction. Our results validate the cold jet as an efficient method to separate astrocytes from neurons in co-culture, and reveals that neurons induce robust gene-expression changes in co-cultured astrocytes.