Glia最新文献

Cover Illustration: Oligodendrocyte binds to laminin on the perivascular basement membrane in the murine cortex at the age of postnatal day 16 (red: CC-1; green: laminin alpha-2; blue: DAPI). (See Sasaki, B., et al, https://doi.org/10.1002/glia.70027)

Spinal cord injury (SCI) results in significant disruption of nerve fibers responsible for transmitting signals between the brain and body, often leading to partial or complete motor, sensory, and autonomic dysfunction below the injury site. Astrocytes are an important component in scar formation, crucial for suppression of injury propagation, effective wound healing, and the regulation of neuronal plasticity. Here, we identify the role of the actin-binding protein Drebrin (DBN) in reactive astrogliosis following SCI. SCI induces the upregulation of DBN in astrocytes, which controls immediate injury containment but also the long-term preservation of tissue integrity and healing in the spinal cord. DBN knockout results in enlarged spinal cord lesions, increased immune cell infiltration, and neurodegeneration. Mechanistically, DBN loss disrupts the polarization of scar border-forming astrocytes, leading to impaired encapsulation of the injury. In summary, DBN serves as a pivotal regulator of SCI outcome by modulating astrocytic polarity, which is essential for establishing a protective barrier confining the lesion site.

Electrical signaling, driven by ion fluxes between intra- and extracellular compartments, is central to brain functioning. Astrocytes provide crucial support by maintaining the homeostasis of water and ions in the brain. This is disrupted in the leukodystrophy Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC). Studies on cultured primary astrocytes and other isolated cell lines point to a central defect in astrocyte volume regulation in MLC. However, cell culture severely alters the properties and polarity of astrocytes. Therefore, whether astrocytes in the intact MLC brain exhibit aberrant physiology related to water and ion homeostasis remains unknown. To investigate astrocyte physiology in intact astrocytes, we performed experiments in acute brain slices from a validated MLC mouse model, the Glialcam-null mouse. We combined viral sensor delivery with two-photon microscopy to study astrocyte volume regulation and associated chloride dynamics. Cortical Glialcam-null astrocytes showed normal intracellular chloride dynamics but reduced volume recovery upon potassium-induced cell swelling. Whole-cell patch-clamp recordings revealed a modestly depolarized resting membrane potential and slower glutamate uptake in Glialcam-null astrocytes. Gap junction coupling of the astrocyte syncytium was modestly reduced, but it remained sufficient to preserve functional electrical isopotentiality. In conclusion, our findings confirm that the previously observed disturbance of astrocyte volume regulation observed in cultured cells is also observed in intact astrocytes in situ, and we uncover additional changes in astrocyte electrophysiological properties. These findings support the concept that dysfunctional astrocyte volume regulation is central to the MLC disease mechanism.

Cover Illustration: Stochastically labeled astrocytes (cyan) and Müller glia (magenta) contacting blood vessels (orange) and neural cell bodies and axons bundles (green) in a mouse retina. (See Holden, JM, et al, https://doi.org/10.1002/glia.70022)

Cholesterol is highly enriched in the myelin sheath and is often dysregulated in neurodegenerative diseases affecting myelin integrity. Despite the prominence of promyelinating drugs targeting sterol synthesis and our increasing knowledge of oligodendrocyte heterogeneity, few studies have defined regional differences in lipid metabolism across the CNS. Previous analyses revealed that spinal cord oligodendroglia have a higher capacity for endogenous cholesterol biosynthesis compared to brain oligodendroglia. Our current findings reveal that, in contrast to spinal cord oligodendroglia, brain oligodendroglia have a higher capacity to uptake and respond to extracellular lipoproteins. Moreover, brain myelin has lower lipid concentrations compared to spinal cord myelin. Comparisons between spinal cord and subregions of the brain revealed that myelin lipid content is correlated to average axon diameter such that regions with smaller diameter axons, such as corpus callosum and cortical gray matter, have myelin with lower cholesterol and phospholipid content compared to regions containing higher diameter axons, including spinal cord and brain stem. When differentiated on synthetic nanofibers in vitro, spinal cord oligodendrocytes maintained a higher cholesterol content compared to brain oligodendrocytes irrespective of fiber diameter but displayed fiber diameter-dependent changes in fatty acid content. Establishment and maintenance of regional differences in myelin composition are supported by the mechanistic target of rapamycin (mTOR) signaling, as deletion of mTOR in oligodendroglia abolishes regional differences in myelin lipid content, with the greatest decreases in spinal cord and brain stem. These data highlight multiple differences in brain and spinal cord lipid metabolism, which result in regionally distinct myelin composition.

Ischemic stroke significantly contributes to global morbidity and disability through a cascade of neurological responses. Microglia, the immune modulators within the brain, exhibit dual roles in exacerbating and ameliorating ischemic injury through neuroinflammatory and neuroprotective roles, respectively. Despite emerging insights into microglia's role in neuronal support, the potential of epigenetic intervention to modulate microglial activity remains largely unexplored. We have previously shown that sodium butyrate, a histone deacetylase inhibitor (HDACi) epigenetically regulates the inflammatory response of microglia after ischemic stroke, and this study was aimed at characterizing the transcriptomic profiles of microglia and their spatial distribution in the stroke brain following HDACi administration. We hypothesized that the administration of HDACi epigenetically modulates microglial activation and a region-specific microglial phenotype in the stroke brain, shifting their phenotype from neurotoxic to neuroprotective and facilitating neuronal repair in the ischemic penumbra. Utilizing a rodent model of stroke, spatial transcriptomics and 3D morphometric reconstruction techniques were employed to investigate microglial responses in critical penumbral regions following HDACi administration. We found HDACi significantly altered the microglial transcriptomic landscape involving biological pathways of neuroinflammation, neuroprotection, and phagocytosis, as well as morphological phenotype, promoting a shift toward reparative, neurotrophic profiles within the ischemic penumbra. These changes were associated with enhanced neuronal survival and reduced neuroinflammation in specific regions in the ischemic brain. By elucidating the mechanisms through which HDACi influences microglial function, our findings propose therapeutic avenues for neuroprotection and rehabilitation in ischemic stroke, and possibly other neurodegenerative conditions that involve microglia-mediated neuroinflammation.

Amyotrophic lateral sclerosis (ALS) is defined by motor neuron death. However, recent research has identified non-cell-autonomous mechanisms, with significant involvement of glia in disease progression. We link previous observations of intracellular protein aggregates in glia to the autophagy pathway, the primary mediator of intracellular degradation of large protein aggregates. While dysfunctional autophagy is reported in ALS motor neurons, pre-clinical and clinical outcomes of autophagy modulators have been inconsistent, indicating the need for a nuanced understanding of autophagy dynamics across CNS cell types and ALS-affected regions. We hypothesized that glial autophagy is defective in ALS, with glial-type-specific dysfunction. To investigate in vivo autophagy dynamics, we intercrossed SOD1^G93A mice with transgenic RFP-EGFP-LC3 autophagy reporter mice, enabling the quantification of autophagy degradation, termed flux. Investigation of autophagy dynamics in SOD1 oligodendrocytes, microglia, and astrocytes at key disease stages uncovered useful insights. While oligodendrocytes seemed to mount effective compensatory autophagic responses to combat mutant SOD1, significantly increased autophagy flux was observed in symptomatic spinal microglia and astrocytes in comparison to controls. Symptomatic SOD1 astrocytes displayed greater autophagy dysfunction compared to microglia, with subcellular analysis revealing cell compartment-specific, transient autophagy defects that returned to control levels by end stage. Interestingly, spinal glia showed more pronounced and earlier autophagy dysfunction compared to motor cortex glia, where autophagy dysfunction emerged later in disease end stage, aligning with greater spinal cord pathology reported in this model. Our results suggest that cell-type- and time-specific targeting might be essential when developing autophagy therapeutics for ALS, with prioritization of astrocytic autophagy modulation.