Defining the molecular identity and morphology of glia limitans superficialis astrocytes in vertebrates.

Astrocytes are a highly abundant glial cell type and perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogeneous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains.

Are we there yet? Exploring astrocyte heterogeneity one cell at a time.

Astrocytes are a highly abundant cell type in the brain and spinal cord. Like neurons, astrocytes can be molecularly and functionally distinct to fulfill specialized roles. Recent technical advances in sequencing-based single cell assays have driven an explosion of omics data characterizing astrocytes in the healthy, aged, injured, and diseased central nervous system.

Temporal and spatial analysis of astrocytes following stroke identifies novel drivers of reactivity.

Astrocytes undergo robust gene expression changes in response to a variety of perturbations, including ischemic injury. How these transitions are affected by time, and how heterogeneous and spatially distinct various reactive astrocyte populations are, remain unclear. To address these questions, we performed spatial transcriptomics as well as single nucleus RNAseq of ~138,000 mouse forebrain astrocytes at 1, 3, and 14 days after ischemic injury.

Defining the molecular identity and morphology of astrocytes in mouse and human.

Astrocytes are a highly abundant glial cell type that perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogenous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains.

Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease.

Introduction: The inositol polyphosphate-5-phosphatase D (INPP5D) gene encodes a dual-specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. Single nucleotide polymorphisms in INPP5D impact risk for developing late onset sporadic Alzheimer's disease (LOAD).

Methods: To assess the consequences of inducible Inpp5d knockdown in microglia of APP /PSEN1 (PSAPP) mice, we injected 3-month-old Inpp5d /Cx3cr1 and PSAPP/Inpp5d /Cx3cr1 mice with either tamoxifen (TAM) or corn oil (CO) to induce recombination.

Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer's disease.

Resolving glial contributions to Alzheimer's disease (AD) is necessary because changes in neuronal function, such as reduced synaptic density, altered electrophysiological properties, and degeneration, are not entirely cell autonomous. To improve understanding of transcriptomic heterogeneity in glia during AD, we used single-nuclei RNA sequencing (snRNA-seq) to characterize astrocytes and oligodendrocytes from apolipoprotein (APOE) Ɛ2/3 human AD and age- and genotype-matched non-symptomatic (NS) brains. We enriched astrocytes before sequencing and characterized pathology from the same location as the sequenced material.

Neurotoxic reactive astrocytes induce cell death via saturated lipids.

Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity.

Neuroinflammatory astrocyte subtypes in the mouse brain.

Astrocytes undergo an inflammatory transition after infections, acute injuries and chronic neurodegenerative diseases. How this transition is affected by time and sex, its heterogeneity at the single-cell level and how sub-states are spatially distributed in the brain remains unclear. In this study, we investigated transcriptome changes of mouse cortical astrocytes after an acute inflammatory stimulus using the bacterial cell wall endotoxin lipopolysaccharide.

Astrocytes.

Philip Hasel and Shane Liddelow introduce astrocytes - glial cells that help to maintain the homeostasis of the central nervous system during development, normal physiology, and aging.

The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences.

The GluN2 subtype (2A versus 2B) determines biophysical properties and signaling of forebrain NMDA receptors (NMDARs). During development, GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. This "switch" is proposed to be driven by distinct features of GluN2 cytoplasmic C-terminal domains (CTDs), including a unique CaMKII interaction site in GluN2B that drives removal from the synapse.

Mixed-species RNA-seq for elucidation of non-cell-autonomous control of gene transcription.

Transcriptomic changes induced in one cell type by another mediate many biological processes in the brain and elsewhere; however, achieving artifact-free physical separation of cell types to study them is challenging and generally allows for analysis of only a single cell type. We describe an approach using a co-culture of distinct cell types from different species that enables physical cell sorting to be replaced by in silico RNA sequencing (RNA-seq) read sorting, which is possible because of evolutionary divergence of messenger RNA (mRNA) sequences. As an exemplary experiment, we describe the co-culture of purified neurons, astrocytes, and microglia from different species (12-14 d).

Author Correction: Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.

This corrects the article DOI: 10.1038/ncomms15132.

Corrigendum: Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system.

This corrects the article DOI: 10.1038/ncomms7761.

Expression of mRNA Encoding Mcu and Other Mitochondrial Calcium Regulatory Genes Depends on Cell Type, Neuronal Subtype, and Ca2+ Signaling.

Uptake of Ca2+ into the mitochondrial matrix controls cellular metabolism and survival-death pathways. Several genes are implicated in controlling mitochondrial Ca2+ uptake (mitochondrial calcium regulatory genes, MCRGs), however, less is known about the factors which influence their expression level. Here we have compared MCRG mRNA expression, in neural cells of differing type (cortical neurons vs.

Mitochondrial Calcium Uptake Modulates Synaptic Vesicle Endocytosis in Central Nerve Terminals.

Presynaptic calcium influx triggers synaptic vesicle (SV) exocytosis and modulates subsequent SV endocytosis. A number of calcium clearance mechanisms are present in central nerve terminals that regulate intracellular free calcium levels both during and after stimulation. During action potential stimulation, mitochondria rapidly accumulate presynaptic calcium via the mitochondrial calcium uniporter (MCU).

Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2.

Forebrain neurons have weak intrinsic antioxidant defences compared with astrocytes, but the molecular basis and purpose of this is poorly understood. We show that early in mouse cortical neuronal development in vitro and in vivo, expression of the master-regulator of antioxidant genes, transcription factor NF-E2-related-factor-2 (Nrf2), is repressed by epigenetic inactivation of its promoter. Consequently, in contrast to astrocytes or young neurons, maturing neurons possess negligible Nrf2-dependent antioxidant defences, and exhibit no transcriptional responses to Nrf2 activators, or to ablation of Nrf2's inhibitor Keap1.

Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system.

How the brain's antioxidant defenses adapt to changing demand is incompletely understood. Here we show that synaptic activity is coupled, via the NMDA receptor (NMDAR), to control of the glutathione antioxidant system. This tunes antioxidant capacity to reflect the elevated needs of an active neuron, guards against future increased demand and maintains redox balance in the brain.

Selective dendritic susceptibility to bioenergetic, excitotoxic and redox perturbations in cortical neurons.

Neurodegenerative and neurological disorders are often characterised by pathological changes to dendrites, in advance of neuronal death. Oxidative stress, energy deficits and excitotoxicity are implicated in many such disorders, suggesting a potential vulnerability of dendrites to these situations. Here we have studied dendritic vs.