Glia最新文献

Glial cells were first defined by Rudolf Virchow in 1856. About 40 years later, glial research had developed into a field distinct from the mainstream study of neurons as the central elements governing brain function. By that time, substantial knowledge about the properties of glial cells had accumulated, exemplified by five important publications by four distinguished investigators: Gustav Retzius, Michael von Lenhossek, Carl Weigert, and Hans Held. These treatises broadly summarized what was known about glial cells, comparing findings from leeches to humans. Practically speaking, these articles represent the foundation of our current knowledge. All five contributions were published in German, which at the time was one of the dominant languages for scientific exchange. This article summarizes and comments on their findings and thus provides insight into what was known about glial cells at that time. More importantly, in the Supporting Information, we provide English translations and original scans of these five publications, making them accessible to an international readership.

Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants are associated with genes highly expressed in astrocytes. However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill-defined. Here, we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from 44 individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag-mass spectrometry. We demonstrate the utility of this resource in examining gene- and pathway-level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC-astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC-derived astrocytes from individuals with AD are concordantly dysregulated in AD brain tissue. This includes increased levels of prefoldin proteins, extracellular matrix factors, COPI-mediated trafficking components and reduced levels of proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC-derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins in astrocytes. This study establishes an experimental system that integrates genetic information with a matched iPSC lines and brain tissue data from a large cohort of individuals to identify genetic contributions to molecular pathways affecting AD risk and resilience.

Glia antigen-presenting cells (APCs) are pivotal regulators of immune surveillance within the retina, maintaining tissue homeostasis and promptly responding to insults. However, the intricate mechanisms underlying their local coordination and activation remain unclear. Our study integrates an animal model of retinal injury, retrospective analysis of human retinas, and in vitro experiments to gain insights into the crucial role of antigen presentation in neuroimmunology during retinal degeneration (RD), uncovering the involvement of various glial cells, notably Müller glia and microglia. Glial cells act as sentinels, detecting antigens released during degeneration and interacting with T-cells via MHC molecules, which are essential for immune responses. Microglia function as APCs via the MHC Class II pathway, upregulating key molecules such as Csf1r and cytokines. In contrast, Müller cells act through the MHC Class I pathway, exhibiting upregulated antigen processing genes and promoting a CD8⁺ T-cell response. Distinct cytokine signaling pathways, including TNF-α and IFN Type I, contribute to the immune balance. Human retinal specimens corroborate these findings, demonstrating glial activation and MHC expression correlating with degenerative changes. In vitro assays also confirmed differential T-cell migration responses to activated microglia and Müller cells, highlighting their role in shaping the immune milieu within the retina. In summary, our study emphasizes the involvement of retinal glial cells in modulating the immune response after insults to the retinal parenchyma. Unraveling the intricacies of glia-mediated antigen presentation in RD is essential for developing precise therapeutic interventions for retinal pathologies.

Neuromyelitis optica spectrum disorders (NMOSD) are severe autoimmune conditions affecting the central nervous system. In a subset of cases, no autoantibodies are detectable with the currently used routine assays. This study aimed to determine whether the levels of expression of aquaporin-4 (AQP4), excitatory amino acid transporter 2 (EAAT2), or complement C3/C3d and C5b-9 in human astrocytes following incubation with patient sera under inflammatory conditions differ between the various NMOSD subtypes and whether such differences can help to identify autoantibody-mediated cases of NMOSD. Levels of AQP4, EAAT2, complement C3/C3d and C5b-9 epitope expression on human astrocytes pretreated with various cytokines were quantitatively analyzed via indirect immunofluorescence after exposure to sera from patients with AQP4-IgG seropositive, MOG-IgG seropositive, and AQP4/MOG-IgG double seronegative NMOSD. Significant differences in AQP4 and C3d epitope expression were observed, with IL-17A, IL-10, and IL-6 pre-treatment notably influencing astrocytic responses. Using uniform manifold approximation and projection (UMAP), patients were classified into clusters corresponding to AQP4-IgG seropositive, MOG-IgG seropositive, or double seronegative NMOSD. These results demonstrate distinct astrocytic staining patterns across NMOSD subtypes, providing a potential diagnostic tool for distinguishing between autoantibody-mediated astrocytopathy and other cases. These findings suggest specific pathogenic mechanisms linked to each NMOSD subtype, which may have implications for tailoring therapeutic strategies based on cytokine involvement and astrocyte reactivity.

Autism spectrum disorder (ASD) is marked by neurobehavioral developmental deficits, potentially linked to disrupted neuron-glia interactions. The astroglia Kir4.1 channel plays a vital role in regulating potassium levels during neuronal activation, and mutations in this channel have been associated with ASD. This study investigates astroglia Kir4.1 as a regulator of neuronal excitability and behavioral abnormalities in rats with autistic-like traits induced by prenatal exposure to valproic acid (VPA). Whole-cell patch-clamp recordings were obtained from pyramidal neurons in the hippocampal CA1 region, showing that inhibition of Kir4.1 channels led to electrophysiological changes indicative of neuronal hyperexcitability, similar to that seen in VPA-exposed neurons. Specifically, there was increased input resistance and voltage threshold, alongside decreased time constant and rheobase. Behavioral assessments after 7 days of intrahippocampal PA6 (5 μg/mL/day) administration revealed significant social withdrawal, heightened anxiety, reduced exploration, and impaired recognition memory, underscoring the behavioral deficits linked to autism. While Kir4.1 inhibition affected excitability, it did not alter the output of CA1 pyramidal neurons in autistic-like rats. These findings emphasize the critical role of astroglia Kir4.1 channels in modulating neuronal excitability and associated behavioral impairments within the VPA-induced autism model, suggesting a promising target for future therapeutic interventions.

Microglia, the parenchymal macrophage of the central nervous system, serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia express CD11c (Integrin αX, Itgax, subunit of complement receptor 4) which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia. We found that CD11c+ microglia track with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is partially dependent upon the TAM receptor AXL. Using selective ablation, we found CD11c+ microglia are not uniquely critical for phagocytic clearance of apoptotic cells. Together, our data suggest that CD11c+ microglia are a transient state induced by developmental apoptosis rather than a specialized subset mediating phagocytic elimination.

At cellular and circuit levels, drug addiction is considered a dysregulation of synaptic plasticity. In addition, dysfunction of the glutamate transporter 1 (GLT-1) in the nucleus accumbens (NAc) has also been proposed as a mechanism underlying drug addiction. However, the cellular and synaptic impact of GLT-1 alterations in the NAc remain unclear. Here we show in the NAc that 10 days withdraw after 5 days treatment with cocaine or amphetamine decreases GLT-1 expression in astrocytes, which results in the prolongation of the excitatory postsynaptic potential (EPSP) decay kinetics in D1 receptor-containing medium spiny neurons (D1R-MSNs). Using the spike timing dependent plasticity (STDP) paradigm, we found that enlargement of EPSP duration results in switching the LTP elicited in control animals to LTD in psychostimulant-treated mice. In contrast to D1-MSNs, D2-MSNs did not display changes in EPSP kinetics and synaptic plasticity. Notably, the psychostimulant-induced synaptic transmission and synaptic plasticity effects were absent in IP3R2^−/− mice, which lack astrocyte calcium signal, but were mimicked by the selective astrocytes stimulation with DREADDs. Finally, ceftriaxone, which upregulates GLT-1, restored normal GLT-1 function, EPSP kinetics, and synaptic plasticity in psychostimulant-treated mice. Therefore, we propose that cocaine and amphetamine increase dopaminergic levels in the NAc, which stimulates astrocytes and downregulates the GLT-1. The decreased GLT-1 function prolonged the EPSP kinetics, leading to the modulation of the STDP, transforming the LTP observed in control animals into LTD in psychostimulant-treated mice. Present work reveals a novel mechanism underlying the synaptic plasticity changes induced by these drugs of abuse.