Glia最新文献

Myelin is a highly complex membranous structure wrapped around axons by oligodendrocytes or Schwann cells in the central and peripheral nervous system, respectively. Fluorescent labeling is widely used to study the structure and dynamics of myelin. Combining structural with functional imaging requires labeling of myelin with red fluorescence, as many functional sensors, including Ca²⁺ indicators and genetically encoded metabolite sensors, fluoresce in the green spectral range. However, in vivo tools enabling red fluorescent labeling of myelinating cells and their myelin sheaths remain limited. Here, we generated a set of seven transgenic mouse lines expressing a membrane-targeted variant of the red fluorescent protein tdTomato in myelinating oligodendrocytes and Schwann cells throughout the nervous system. The mouse lines provide a variety of expression patterns ranging from wide-spread labeling of myelin to a rather sparse expression, the latter enabling visualization of individual oligodendrocytes and their associated myelin sheaths. In the peripheral nervous system, the pattern of fluorescence in sciatic nerves indicates predominant localization of tdTomato to non-compact myelin compartments including the inner and outer tongues, paranodal loops and Schmidt-Lanterman incisures. In summary, our work provides a set of novel mouse lines with myelin labeled by red fluorescence, which are compatible with diverse imaging modalities in the green spectral range enabling integrated structural and functional imaging.

Krabbe disease (KD) is a lysosomal storage disorder characterized by severe peripheral demyelination caused by mutations in galactosylceramidase (GALC), leading to the accumulation of galactosylceramide and psychosine. Although psychosine toxicity is central to KD pathology, additional mechanisms likely contribute to myelin dysfunction. Because Schwann cells (SCs) play a critical role in myelin maintenance, and GALC deficiency disrupts lysosomal function, we hypothesized that autophagy is altered in SCs during KD progression. Using a SC-specific Galc conditional knockout (Galc SC cKO) mouse model, we identified early changes in autophagy-related protein levels and increased autophagosome abundance during the pre-symptomatic phase, prior to detectable myelin abnormalities. To assess whether autophagy contributes to disease progression, we selectively deleted Atg7, an essential regulator of canonical autophagy, in SCs. Atg7 deletion alone did not affect myelin or behavior, but its loss in Galc SC cKO mice markedly worsened disease severity. Atg7-Galc SC cKO mice exhibited significantly thinner myelin and pronounced deficits in motor performance and nerve conduction, accompanied by altered steady-state levels of autophagy-associated proteins and functional decline. Notably, Atg7 deletion in Galc SC cKO mice did not further increase macrophage abundance, suggesting that the worsened myelin phenotype occurs without additional macrophage recruitment at this stage. Together, these findings demonstrate that autophagy-associated changes occur early in KD and ATG7-dependent pathways play a protective role during disease progression. Modulating ATG7-dependent pathways may therefore warrant further investigation as a strategy to support myelin maintenance in KD and related lysosomal disorders.

Myelin has the capacity to affect synapse number or plasticity across the lifespan. We report that disrupting oligodendrocyte (OL) and myelin maintenance from P57 (Plp-CreER^T2:: Myrf^fl/fl mice) induces myelin loss and impairs action potential conduction and gross motor performance. By studying sparsely labeled layer V pyramidal neurons in the primary motor cortex of P57 + 60 mice, we determined that apical and basal dendritic spine densities were normal; however, more were large, stable mushroom spines that generated larger amplitude miniature excitatory postsynaptic currents. When we instead prevented OL and myelin addition from P57 (Pdgfrα-CreER:: Myrf^fl/fl mice), action potential conduction velocity, gross motor performance, and spine densities were normal; however, basal dendritic spine morphology was changed. Without adult myelination, the basal dendrites of P57 + 60 mice retained the morphological characteristics of dendrites in P57 + 0 mice, which have a higher proportion of thin, plastic spines. These data indicate that existing myelin imposes limits on the proportion of spines that become mushroom spines, allowing neurons to remain plastic, while adult myelination is required for spine stabilization within the basal but not apical dendritic compartment. These data show that myelin regulates synaptic plasticity within the motor circuit and offer a potential mechanism by which myelination can influence motor skill learning and/or recall.

The zebrafish telencephalon is an excellent model for adult neurogenesis under physiological and regenerative conditions, as many pathways regulating neural stem cell behavior are conserved with mammalian neurogenic niches. Resident radial glial cells (RGCs) serve as neural stem cells in the adult brain and are readily accessible in vivo, because forebrain eversion repositions the ventricular zone to the dorsal surface. Recent studies have revealed substantial heterogeneity among RGCs, including activation-primed cells and deeply quiescent states during homeostasis. Here, we first review the evidence that four mechanisms control quiescence in pallial RGCs: Notch3-mediated lateral inhibition, the neuronal bone morphogenetic protein (BMP)-Id1 axis, the nuclear receptor Nr2f1b, and the secreted factor Midkine-a. The evidence supporting them is unequal, and we state its level for each before asking whether they act together. Notch-mediated lateral inhibition and neuronal BMP-Id1 signaling converge on her4.1, the clearest documented interaction among them, whereas Nr2f1b establishes a deeper dormancy program that resists Notch and BMP inhibition and protects a reserve stem cell pool. Midkine-a is proposed to reinforce quiescence, pending functional validation. Finally, we propose as a hypothesis that these mechanisms act as partially redundant inputs whose relative contributions determine quiescence depth and vary along the antero-posterior axis of the pallium. Together, these findings reframe quiescence as a spectrum of actively maintained conditions rather than a passive default state. These mechanisms are conserved across vertebrates, with implications for understanding why mammalian neural stem cell pools decline with age and injury.

Myelin regulates neural signaling not only by enabling fast conduction but also by dynamically tuning axonal conduction velocity (CV) and thereby shaping spike timing. While activity-dependent myelination is thought to optimize neural communication, how changes in myelin translate into altered single-cell dynamics and plasticity remains unclear. Using a computational modeling approach, we show that disruptions of axonal CV reorganize presynaptic input correlations, leading to systematic changes in postsynaptic excitability, excitation–inhibition balance, and spike-timing-dependent plasticity. By spanning CV regimes associated with healthy myelination, demyelination, and excessive myelination, our simulations illustrate how both deficient and excessive CV could induce maladaptive neuronal dynamics. The incorporation of firing-rate homeostasis into our models further suggests distinct neuronal dynamic consequences for acute versus chronic myelin disruption. Ultimately, these results suggest that axonal CV may serve as a key mechanistic link between myelin plasticity and neural computation, offering a principled framework to interpret the functional consequences of myelin dysregulation in health and disease.

Aging-associated cognitive decline is closely linked to dysregulated glial activity and chronic neuroinflammation, which together constrain neuronal plasticity. Astrocytes and microglia are key regulators of the brain extracellular matrix (ECM), including perineuronal nets (PNNs), whose accumulation during aging contributes to reduced synaptic flexibility. Targeting ECM–glia interactions therefore represents a promising strategy to modulate neuroinflammatory and plasticity-related processes. Here, we investigated the effects of long-term oral administration of 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan and chondroitin sulfate synthesis, on glial reactivity, ECM remodeling, and cognitive function in aged mice (20–22 months). Aging was associated with PNN remodeling alongside pronounced astrocytic and microglial activation and infiltration of peripheral immune cells. Chronic 4-MU treatment reduced PNN accumulation to levels observed in younger (10-month-old) mice, indicating effective ECM remodeling. Notably, this was accompanied by a marked attenuation of astrocyte and microglial activation and a reduction in immune cell infiltration, suggesting a broad normalization of the neuroinflammatory milieu. Functionally, these glia-associated changes were paralleled by improved recognition memory, with treated aged mice performing at or above the level of younger controls. Long-term 4-MU administration was well tolerated, with no evident adverse effects. Together, our findings identify ECM modulation as a mechanism to regulate glial reactivity and neuroimmune interactions in the aging brain. By targeting hyaluronan-dependent pathways, 4-MU links ECM remodeling to suppression of neuroinflammation and restoration of cognitive function, highlighting its therapeutic potential in age-related neurodegenerative processes.

Astrocyte diversity is currently expanding both between and within specific brain regions. Here, we assessed the spatial distribution and transcriptomic profile of two hippocampal astrocyte subpopulations, defined by combinatorial expression of the cell surface astrocyte markers ACSA-1 or GLAST/SLC1A3, and ACSA-2 or ATP1B2. Fluorescence activated cell sorting and genome-wide transcriptomics by bulk RNAseq uncovered distinct transcriptional signatures of the two astrocyte subsets and highlighted heterogeneous responses during aging. The most abundant ATP1B2/GLAST double-positive astrocytes corresponded to functionally specialized glial cells with increased protein glycosylation and stable gene expression patterns. Signatures related to mitochondrial respiration and cholesterol metabolism were induced during aging in ATP1B2 single-positive astrocytes, while cell adhesion genes from the γ-protocadherin cluster were repressed in double-positive astrocytes. Heterochronic co-culture assays with primary neurons show the loss of synaptogenic function of old ATP1B2/GLAST astrocytes. Our results complement previous studies demonstrating the presence of morphological and molecular astrocyte heterogeneity within the hippocampus, and uncover differences among astrocyte subsets in their transcriptomic response to aging.